JP4727233B2 - Ring-substituted 8-aminoquinoline derivatives as antimalarials - Google Patents

Description

Field of Invention

  The present invention relates to the development of novel 8-aminoquinoline analogues in the treatment and prevention of malaria, which compounds have broad activity against the blood and tissue stages of human malaria parasites, whereby these compounds are malaria. The development of these compounds as ideal antimalarial drugs would be extremely attractive for the cure and prevention of cancer, and it is believed that single drug therapy could result in the suppression of malaria infection and a radical cure.

［式中、ＲはＨ、１〜８個の炭素原子を含む直鎖アルコキシ基、３〜７個の炭素原子を含む分枝鎖アルキル基、３〜１５個の炭素原子を含むシクロアルキル基、フェノキシ、および置換フェノキシ基を表し、Ｒ_１はＨ、ＣＨ_３、Ｃ_２Ｈ_５を表し、Ｒ_２は１〜５個の炭素を含む直鎖アルキル基、分枝アルキル基、および３〜１５個の炭素原子を含むシクロアルキル基を表し、Ｒ_３は種々の（Ｒ）−および（Ｓ）−アミノ酸またはＬ−非天然アミノ酸を表す］
の２−アルキル−４，５−二置換−６−メトキシプリマキン類似体、およびその薬理学上許容される塩（ここで、塩を形成する酸は本質的に有機であっても無機であってもよい）の合成に関する。キノリン環のＣ−２位における独特かつ直接的な誘導体化によって得られるこれらの８−アミノキノリン種の化合物は、宿主の血液、組織、または血液と組織に存在し得る原虫に対してそれらの生物活性を示すことにより、マラリアの治療において既存の化学療法アプローチに改良を与えるものと考えられる。このような広域活性を有するこれら化合物の抗マラリア薬としての開発により、あらゆる種のヒトマラリア感染の抑制ならびに根治的治癒のための単一薬物治療を提供し得る分子が得られるであろう。 The present invention relates to a ring-substituted 8-aminoquinoline analog useful as an antimalarial drug and a method for producing the same. The present invention in particular has the formula 1 which appears to provide an improved means for malaria chemotherapy:

[Wherein R is H, a linear alkoxy group containing 1 to 8 carbon atoms, a branched alkyl group containing 3 to 7 carbon atoms, a cycloalkyl group containing 3 to 15 carbon atoms, Represents phenoxy and substituted phenoxy groups, R ₁ represents H, CH ₃ , C ₂ H ₅ , R ₂ represents a linear alkyl group containing 1 to 5 carbons, a branched alkyl group, and 3 to 15 And R ₃ represents various (R)-and (S) -amino acids or L-unnatural amino acids]
2-alkyl-4,5-disubstituted-6-methoxyprimaquine analogs, and pharmacologically acceptable salts thereof, wherein the acid forming the salt is essentially organic or inorganic Also relates to the synthesis of These 8-aminoquinoline species compounds, obtained by unique and direct derivatization at the C-2 position of the quinoline ring, have been shown to their organisms against host blood, tissues, or protozoa that may be present in blood and tissues. By showing activity, it is thought to improve existing chemotherapy approaches in the treatment of malaria. The development of these compounds with such broad activity as antimalarial drugs will provide molecules that can provide a single drug treatment for the suppression of all types of human malaria infection as well as for radical cure.

Background of the Invention

  Currently, the occurrence of widespread infectious diseases threatens the health management system of many countries. Malaria caused by protozoa belonging to the genus Plasmodium is one of the most serious parasitic diseases. According to World Health Organization (WHO) estimates, nearly 4 billion people are at risk of malaria, mostly in tropical / poor countries. Each year, 2 to 3 million people (mostly children) die from malaria and related complications in over 100 countries. Malaria has the highest number of deaths in the sub-Saharan Africa, where one in every five children is malaria. Women are particularly susceptible during pregnancy. They are also more likely to die of the disease, miscarriage, or give birth to premature low-weight infants (Kevin, B. J. Drugs, 59, p 719, 2000). In India alone, 2.5 to 2.8 million malaria cases are reported each year. Civil war, massive movement of people, climate and environmental changes, inadequate and worsening hygiene regimes, increasing pesticide resistance and drug resistance all combine to bring about a relapse of malaria. Thus, malaria remains a major impediment to human health in the tropics and subtropics. The world's estimated annual cost for malaria (1995) is about US $ 2 billion, including that related to labor loss. However, the annual estimated expenditure for research, prevention and treatment of malaria is about US $ 84 million, indicating that more effort is needed to combat this infection.

  The four parasites identified as the cause of human malaria are Plasmodium falciparum, Plasmodium falciparum (P. vivax), Plasmodium falciparum (P. ovale) and Plasmodium falciparum. It is a protozoan (P. malariae). However, Plasmodium falciparum and oval malaria parasites account for more than 95% of the world's malaria cases, and P. falciparum causes the most serious problems as a result of its prevalence, toxicity and drug resistance, and almost all deaths Is attributed to this single parasite species. Malaria infections caused by Plasmodium falciparum are endemic in major regions of Africa, sub-Saharan Africa and East Asian countries, but Plasmodium falciparum is a causative species mainly in the Indian subcontinent. The disease can be treated within 48 hours, and if delayed diagnosis and treatment can cause fatal complications. Malaria re-emerged as the largest infectious killer and is now the World Insurance Organization's top priority tropical disease.

  There are various stages in the life cycle of the malaria parasite, each stage having varying degrees of sensitivity to available antimalarial drugs. Currently available antimalarials are conveniently available in the following two categories: blood schizont antimalarials that exhibit their biological activity against the erythrocytic (blood) phase of malaria parasites and human malaria parasites. Are classified as tissue killing schizont antimalarials that exhibit their antimalarial activity against the extra-erythrocytic (tissue) phase of erythrocytes. All of these available antimalarial drugs have declined in their ability to treat infection and have become inadequate for the treatment of malaria infection. P. falciparum has developed resistance to the majority of blood killing agents such as chloroquine and melfloquine. On the other hand, available tissue killing agents such as primaquine are relatively ineffective against blood schizonts. Furthermore, due to the toxicity of primaquin, it is necessary to administer divided doses over 14 days to achieve a radical healing effect in humans. These problems could be alleviated by the development of compounds with high blood schizont activity comparable to those of chloroquine and mefloquine while retaining the tissue killing activity of 8-aminoquinoline. This allows for single drug treatment for the suppression of malaria infection and for radical cure. The logical lead compound for this study is primaquine and is well supported by the following findings: (1) 8-aminoquinoline is the only compound species that has been shown to successfully treat recurrent malaria (2) 8-aminoquinolines such as primaquine are easy to synthesize and inexpensive to manufacture; (3) 8-aminoquinolines such as primaquine include the blood and tissue phases of the life cycle of human malaria. Be the only drug available to show activity against any stage; (4) Primaquine, an 8-aminoquinoline, has been shown to be effective against drug-resistant strains of Plasmodium falciparum thing.

  Despite more than 60 years of research effort, malaria is still one of the world's leading causes of death. The vast majority of people with malaria belong to the social / national poor and cannot receive expensive treatment. One factor in the development of resistance to the majority of drugs is thought to be a low patient dose. Thus, costly multi-drug therapy is eliminated and a single drug helps reduce the cost of treatment. This cost reduction will lead to an increase in patient dose. This will have better results for the prevention, transmission and treatment of malaria.

Object of the invention

  The main object of the present invention is to provide a process for the preparation of ring-substituted 8-aminoquinoline analogues.

  Another main object of the present invention is to provide 8-aminoquinoline analogues that exhibit excellent antimalarial activity against drug-sensitive and multi-drug resistant parasites.

Another object of the present invention is to provide ring-substituted 8-aminoquinoline analogs with LD ₅₀ values greater than 400 mg / kg body weight.

  Yet another object of the present invention is to provide peptide derivatives of 8-aminoquinoline with reduced toxicity.

  Another object of the present invention is to provide 8-aminoquinoline analogs with low methemoglobin toxic side effects.

Summary of the Invention

［式中、ＲはＨ、１〜８個の炭素原子を含む直鎖アルコキシ基、３〜７個の炭素原子を含む分枝鎖アルキル基、３〜１５個の炭素原子を含むシクロアルキル基、フェノキシ、および置換フェノキシ基を表し、Ｒ_１はＨ、ＣＨ_３、Ｃ_２Ｈ_５を表し、Ｒ_２は１〜５個の炭素を含む直鎖アルキル基、分枝アルキル基、および３〜１５個の炭素原子を含むシクロアルキル基を表し、Ｒ_３は種々の（Ｒ）−および（Ｓ）−アミノ酸またはＬ−非天然アミノ酸を表す］
の２−アルキル−４，５−二置換−６−メトキシプリマキン類似体、およびその薬理学上許容される塩（ここで、塩を形成する酸は本質的に有機であっても無機であってもよい）の合成に関する。キノリン環のＣ−２位における独特かつ直接的な誘導体化によって得られるこれらの８−アミノキノリン種の化合物は、宿主の血液、組織、または血液と組織に存在し得る原虫に対してそれらの生物活性を示すことにより、マラリアの治療において既存の化学療法アプローチに改良を与えるものと考えられる。このような広域活性を有するこれら化合物の抗マラリア薬としての開発により、あらゆる種のヒトマラリア感染の抑制ならびに根治的治癒のための単一薬物治療を提供し得る分子が得られるであろう。 The present invention relates to ring-substituted 8-aminoquinoline analogs useful as antimalarials and methods for their production. Specifically, the present invention may provide an improved means for malaria chemotherapy:

[Wherein R is H, a linear alkoxy group containing 1 to 8 carbon atoms, a branched alkyl group containing 3 to 7 carbon atoms, a cycloalkyl group containing 3 to 15 carbon atoms, Represents phenoxy and substituted phenoxy groups, R ₁ represents H, CH ₃ , C ₂ H ₅ , R ₂ represents a linear alkyl group containing 1 to 5 carbons, a branched alkyl group, and 3 to 15 And R ₃ represents various (R)-and (S) -amino acids or L-unnatural amino acids]
2-alkyl-4,5-disubstituted-6-methoxyprimaquine analogs, and pharmacologically acceptable salts thereof, wherein the acid forming the salt is essentially organic or inorganic Also relates to the synthesis of These 8-aminoquinoline species compounds, obtained by unique and direct derivatization at the C-2 position of the quinoline ring, have been shown to their organisms against host blood, tissues, or protozoa that may be present in blood and tissues. By showing activity, it is thought to improve existing chemotherapy approaches in the treatment of malaria. The development of these compounds with such broad activity as antimalarial drugs will provide molecules that can provide a single drug treatment for the suppression of all types of human malaria infection as well as for radical cure.

Detailed description of the invention

  Thus, the present invention relates to the development of novel 8-aminoquinoline analogs in the treatment and prevention of malaria, and due to the widespread activity against the blood and tissue stages of human malaria parasites, these compounds are extremely useful in the cure and prevention of malaria. It would be attractive and the development of these compounds as ideal antimalarial drugs could lead to the suppression of malaria infection as well as radical cure by single drug therapy.

［式中、ＲはＨ、１〜８個の炭素原子を含む直鎖アルコキシ基、３〜７個の炭素原子を含む分枝鎖アルキル基、３〜１５個の炭素原子を含むシクロアルキル基、フェノキシ、および置換フェノキシ基を表し、Ｒ_１はＨ、ＣＨ_３、Ｃ_２Ｈ_５を表し、Ｒ_２は１〜５個の炭素を含む直鎖アルキル基、分枝アルキル基、および３〜１５個の炭素原子を含むシクロアルキル基を表し、Ｒ_３は種々の（Ｒ）−および（Ｓ）−アミノ酸またはＬ−非天然アミノ酸を表す］
の環置換８−アミノキノリン類似体が提供される。 Therefore, Formula 1:

[Wherein R is H, a linear alkoxy group containing 1 to 8 carbon atoms, a branched alkyl group containing 3 to 7 carbon atoms, a cycloalkyl group containing 3 to 15 carbon atoms, Represents phenoxy and substituted phenoxy groups, R ₁ represents H, CH ₃ , C ₂ H ₅ , R ₂ represents a linear alkyl group containing 1 to 5 carbons, a branched alkyl group, and 3 to 15 And R ₃ represents various (R)-and (S) -amino acids or L-unnatural amino acids]
Of the ring-substituted 8-aminoquinoline analogs.

に示されるものである、上記の環置換８−アミノキノリン類似体が提供される。 According to one embodiment of the invention, R, R ₁ , R ₂ and R ₃ of the compound of formula 1 are:

The above ring-substituted 8-aminoquinoline analogs are provided as shown in

  According to another embodiment of the present invention, there is provided a ring-substituted 8-aminoquinoline analog wherein the compound of formula 1 is effective against Plasmodium berghei infection for 4 days at doses ranging from 10-100 mg.

  According to another embodiment of the present invention, there is provided a ring-substituted 8-aminoquinoline analog wherein the compound of formula 1 is effective against Plasmodium yoelii infection at doses ranging from 10-100 mg for 4 days.

According to another embodiment of the present invention there is provided a ring-substituted 8-aminoquinoline analog wherein the LD ₅₀ of the compound of formula 1 is greater than 400 mg / kg body weight.

  According to another embodiment of the present invention, a ring-substituted 8-aminoquinoline analog is provided wherein said analog does not cause methemoglobin (MetHb) toxicity.

According to another embodiment of the present invention, a pharmaceutically effective amount of a ring-substituted 8-aminoquinoline analog wherein R is H, a linear alkoxy group containing 1 to 8 carbon atoms, 3 to 7 R ₁ represents H, CH ₃ and C ₂ H ₅ ; R ₂ represents a branched chain alkyl group containing 3 carbon atoms, a cycloalkyl group containing 3 to 15 carbon atoms, a phenoxy, and a substituted phenoxy group; Represents a linear alkyl group containing 1 to 5 carbons, a branched alkyl group, and a cycloalkyl group containing ₃ to 15 carbon atoms, and R ₃ represents various (R)-and (S) -amino acids. Or represents an L-unnatural amino acid] and a pharmacologically acceptable additive is provided.

  According to another embodiment of the invention, the pharmaceutically acceptable additive is lactose, mannitol, sorbitol, microcrystalline cellulose, sucrose, sodium citrate, dicalcium phosphate or any other of similar nature. Or an acceptable diluent selected from the group of suitable combinations thereof; tragacanth gum, gum arabic, methylcellulose, gelatin, polyvinylpyrrolidone, starch or any other component of similar nature, or suitable combinations thereof A binder selected from the group of: agar, calcium carbonate, sodium carbonate, silicate, alginic acid, corn starch, potato tapioca starch, primogel or any other component of similar nature, alone or suitably An excipient selected from the group of combinations; Lubricant selected from the group of gnesium, calcium stearate or steorote, talc, solid polyethylene glycol, sodium lauryl sulfate or any other component of similar nature; acetyl alcohol, glyceryl monostearate or other A wetting agent selected from the group of any pharmaceutically acceptable flavors, or suitable combinations thereof; selected from the group of kaolin, bentonite clay or any other pharmaceutically acceptable flavors, or suitable combinations thereof A retardant that is selected from the group of waxes, paraffin or any other pharmaceutically acceptable flavor, or suitable combinations thereof.

に示されるものである環置換８−アミノキノリン類似体を含む抗マラリア組成物が提供される。 According to another embodiment of the present invention, R, R ₁ , R ₂ and R ₃ of the compound of formula 1 are:

An antimalarial composition comprising a ring-substituted 8-aminoquinoline analog that is shown in

  According to another embodiment of the present invention, an antimalarial composition having a broad range of antimalarial activity with respect to the blood stage and tissue stage of the malaria parasite is provided.

  According to another embodiment of the present invention, an antimalarial composition effective against a resistant strain of human malaria parasite is provided.

  According to another embodiment of the present invention, the ring-substituted 8-aminoquinoline analog of Formula 1 is administered at a dose ranging from 10 to 100 mg for 4 days. Antimalarial compositions that are effective against berghei infection are provided.

  According to another embodiment of the present invention, there is provided an antimalarial composition wherein a ring-substituted 8-aminoquinoline analog of formula 1 is effective against P. yoelii infection at a dose in the range of 10-100 mg for 4 days. Is done.

According to another embodiment of the present invention, there is provided an antimalarial composition wherein the LD ₅₀ of the compound of formula 1 is about 400 mg / kg body weight.

  However, since this molecule is not toxic, higher doses can be applied depending on the degree of malaria infection.

  According to another embodiment of the present invention there is provided an antimalarial composition wherein the ring-substituted 8-aminoquinoline analog of formula 1 does not produce methemoglobin (MetHb) toxicity.

  According to another embodiment of the present invention, there is provided said composition in the form of syrup / tablet / capsule / powder / injection.

［式中、ＲはＨ、１〜８個の炭素原子を含む直鎖アルコキシ基、３〜７個の炭素原子を含む分枝鎖アルキル基、３〜１５個の炭素原子を含むシクロアルキル基、フェノキシ、および置換フェノキシ基を表し；Ｒ_１はＨ、ＣＨ_３およびＣ_２Ｈ_５を表し；Ｒ_２は１〜５個の炭素を含む直鎖アルキル基、分枝アルキル基、および３〜１５個の炭素原子を含むシクロアルキル基を表し、かつ、Ｒ_３は種々の（Ｒ）−および（Ｓ）−アミノ酸またはＬ−非天然アミノ酸を表す］
の環置換８−アミノキノリン類似体、およびその薬理学上許容される塩の製造方法であって、ここで、塩を形成する酸は本質的に有機であっても無機であってもよく、
ａ．８−ニトロキノリンとアルキルカルボン酸とを、非プロトン性溶媒中、硫酸、硝酸銀および過硫酸アンモニウムの存在下、還流温度にて５分〜１時間の範囲の時間反応させて、反応混合物から環置換８−アミノキノリンを単離すること；
ｂ．工程（ａ）で得られた環置換８−アミノキノリンと貴金属触媒および水素とを加圧下で反応させて環置換８−ニトロキノリンを得ること；
ｃ．環置換８−アミノキノリンと２−（４−ブロモペンチル）−１，３−イソインドリンジオンおよびトリエチルアミンとを、１００〜１４０℃の範囲の温度で３〜２１時間の範囲の時間反応させてイソインドリンジオン誘導体を得ること；
ｄ．工程（ｃ）で得られたイソインドリンジオン誘導体とヒドラジン水和物とをアルコール系溶媒中で反応させて環置換Ｎ８−（４−アミノ−１−メチルブチル）−８−キノリンアミンを得ること；
ｅ．工程（ｄ）で得られたＮ８−（４−アミノ−１−メチルブチル）−８−キノリンアミンとＮ−保護アミノ酸およびジシクロヘキシルカルボジイミドとを、クロロアルカン溶媒中、１０〜５０℃の範囲の温度で反応させ、環置換保護アミノ酸キノリン誘導体を単離した後、その分子のアミノ酸部分を脱保護して式１の化合物を得ること
を含んでなる方法が提供される。 Thus, according to the present invention, the formula 1:

[Wherein R is H, a linear alkoxy group containing 1 to 8 carbon atoms, a branched alkyl group containing 3 to 7 carbon atoms, a cycloalkyl group containing 3 to 15 carbon atoms, Represents phenoxy and substituted phenoxy groups; R ₁ represents H, CH ₃ and C ₂ H ₅ ; R ₂ represents a linear alkyl group containing 1 to 5 carbons, a branched alkyl group, and 3 to 15 And R ₃ represents various (R)-and (S) -amino acids or L-unnatural amino acids]
Wherein the acid forming the salt may be organic or inorganic in nature, wherein the ring-forming 8-aminoquinoline analog and the pharmacologically acceptable salt thereof are:
a. 8-nitroquinoline and an alkyl carboxylic acid are reacted in an aprotic solvent in the presence of sulfuric acid, silver nitrate and ammonium persulfate at a reflux temperature for a time ranging from 5 minutes to 1 hour, and from the reaction mixture, ring substitution 8 Isolating aminoquinoline;
b. Reacting the ring-substituted 8-aminoquinoline obtained in step (a) with a noble metal catalyst and hydrogen under pressure to obtain a ring-substituted 8-nitroquinoline;
c. A ring-substituted 8-aminoquinoline is reacted with 2- (4-bromopentyl) -1,3-isoindolinedione and triethylamine at a temperature in the range of 100 to 140 ° C. for a time in the range of 3 to 21 hours to give isoindoline. Obtaining a dione derivative;
d. Reacting the isoindolinedione derivative obtained in step (c) with hydrazine hydrate in an alcohol solvent to obtain a ring-substituted N8- (4-amino-1-methylbutyl) -8-quinolinamine;
e. Reaction of N8- (4-amino-1-methylbutyl) -8-quinolinamine obtained in step (d) with N-protected amino acid and dicyclohexylcarbodiimide at a temperature in the range of 10 to 50 ° C. in a chloroalkane solvent. And isolating the ring-substituted protected amino acid quinoline derivative, followed by deprotecting the amino acid portion of the molecule to provide a compound of Formula 1 is provided.

  According to another embodiment of the present invention, the alkylcarboxylic acid is selected from the group consisting of trimethylacetic acid, isobutyric acid, cyclohexanecarboxylic acid, and 1-adamantanecarboxylic acid.

  According to another embodiment of the present invention, the 8-nitroquinoline is 6-methoxy-8-nitroquinoline, 5,6-dimethoxy-8-nitroquinoline, 4-ethyl-5-pentoxy-6-methoxy- Selected from 8-nitroquinoline, 4-ethyl-5-octoxy-6-methoxy-8-nitroquinoline, and 4-methyl-5,6-dimethoxy-8-nitroquinoline.

  According to another embodiment of the present invention, the catalyst used in the reduction step (b) is Raney nickel.

  According to another embodiment of the invention, the reduction is performed in a Parr hydrogenator at a pressure in the range of 40-50 psi.

  According to another embodiment of the invention, the alcohol solvent used is ethyl alcohol.

  According to another embodiment of the invention, the chloroalkane solvent is selected from dichloromethane.

  According to another embodiment of the invention, the deprotection of the benzyl ester of the amino acid part of the molecule in step (e) is carried out in the presence of Pd—C in methanol in the presence of hydrogen gas.

  According to another embodiment of the invention, the deprotection of the t-Boc protected amino acid is performed in the presence of methanolic HCl.

に示されるものである。 According to another embodiment of the present invention, R, R ₁ , R ₂ and R ₃ of formula 1 are:

It is shown in

  According to another embodiment of the invention, the compound of formula 1 is effective against P. berghei, P. yoelii infection for 4 days at doses ranging from 10 to 100 mg.

According to another embodiment of the invention, the LD ₅₀ of the compound of formula 1 is 400-450 mg / kg body weight.

  According to another embodiment of the invention, the ring-substituted 8-aminoquinoline analog does not produce methemoglobin (MetHb) toxicity.

  According to another embodiment of the present invention, a subject in need thereof is administered a pharmaceutically effective dose of a ring-substituted 8-aminoquinoline analog of formula 1 as defined in claim 1 pharmaceutically acceptable. A single drug method is provided for treatment by administering to a mammal together with a salt, carrier or additive.

  According to another embodiment of the invention, the subject is a mammal, preferably a human.

  According to another embodiment of the present invention, the compound of formula 1 is effective against P. berghei and P. yoelii infection for 4 days at doses ranging from 10-100 mg.

According to another embodiment of the invention, the LD ₅₀ of the compound of formula 1 is in the range of 400-450 mg / kg body weight.

  According to another embodiment of the present invention, the composition has a broad range of antimalarial activity against the blood and tissue stages of Plasmodium.

  According to another embodiment of the invention, the composition is effective against resistant strains of Plasmodium human malaria.

  Most of the available antimalarials are ineffective and ineffective in treating malaria infection. The development of resistance by Plasmodium falciparum has been reported for the majority of blood killing agents. Furthermore, available tissue killing agents are highly toxic for use in humans as causative agents and gameticides.

Primaquine, ^i.e., N 8 - (4-amino-1-methylbutyl) -6-methoxy-8-quinolinamine are very effective tissue schizontocidal drugs, direct and immediate for all species of Plasmodium Has a sex killing action. This drug also has blood killing activity only at toxic doses that are dangerous for humans. Its high toxicity properties [especially methemoglobinemia and hemolysis in individuals who are generally deficient in glucose 6-phosphate dehydrogenase (G-6PD)] have markedly prevented clinicians from using it safely. The inventors have published a recent publication (LaMontagne, M.) that substitution of the methoxy group at the C-2 position of the quinoline ring of primaquine derivatives has resulted in much superior analogs with exceptional tissue and blood killing activity. (P., Blumbergs, P., Smith DCJ Med. Chem. 32, p 1728, 1989). There are three prior reports on the synthesis of 2-substituted primaquine derivatives [Shetty, RV, Wetter, WP, Blanton, CDJ Med. Chem. 20, p 1349, 1977, substitution at the C-2 position with various benzyloxy and When it is a benzylthio group], [Shetty, RV, Blanton, CDJ Med. Chem. 21, p 995, 1978, substitution at the C-2 position is CH ₂ C ₆ H ₅ , OCH ₃ , NH ₂ , N (CH _{3 3} , Cl, C ₂ H ₅ , CH═CH ₂ , NHCOCH ₃ ] and [Carroll, F. I, Berrang, BD, Linn, CPJ Med. Chem. 23, p 581, 1980, C-2 When the substitution at the position is C ₂ H ₅ , CH═CH ₂ , CH ₃ , CH ₂ CH ₂ Br]. However, none of these compounds showed excellent biological activity.

  According to the present invention, radical homolytic free radical reaction for providing novel 2-alkyl-8-aminoquinoline, 5-alkyl-8-aminoquinoline and 2,5-dialkyl-8-aminoquinoline derivatives [scheme] 1] and the surprisingly potent broad spectrum antimalarial activity of analogs belonging to the 2-alkyl-8-aminoquinoline system is disclosed.

  The basis for the synthesis of these compounds is as follows: One of the major metabolic degradation pathways known for the quinoline moiety results in an oxidative biotransformation at the C-2 position, which is converted to 1H-2-oxoquinoline. Convert to. This pathway is supported by a recent study conducted by Mirghani and collaborators who identified 2-quininone (known to show phototoxic side effects) as one of the major metabolites of quinine (Mirghani RA, Ericsson O., Cook J., Yu P., Gustafsson LLJ Chromatogr. B Biomed. Sci. Appl. 2001, 754, 57-64). Furthermore, the high antimalarial activity associated with mefloquine and related compounds is known to be induced by substitution of the trifluoromethyl group at the C-2 position of the quinoline ring, which is inactive and phototoxic 1H-2 -Prevent bioconversion to oxoquinoline. Surprisingly, although such metabolic pathways are not known for primaquine, primaquine 2-alkoxy (LaMontagane, MP, Blumberg, P., Smith, DCJ Med. Chem. 1989, 32, 1728) -1732) and 2-alkyl (Schmidt, LH Antimicrob. Agents Chemother. 1983, 24, 615-652) substituents resulted in an overall improvement in therapeutic efficacy. It is not yet clear whether these compounds show improved efficacy by blocking the proposed metabolic pathway. Based on these findings, the inventors have found that substitution of metabolically stable, bulky alkyl groups at the C-2 position of the primoquinone quinoline ring is a C-2 metabolic pathway in which they are described with respect to the quinoline ring. It is hypothesized that it would be possible to provide analogs with improved therapeutic effects due to the inability to receive it.

The 8-nitroquinoline required for the synthesis of the ring-substituted-8-nitroquinoline (Scheme 1) can be prepared from the appropriate nitroaniline by the Skraup synthesis (Jain, R., Jain, S. , Gupta, RC, Anand, N., Dutta, GP and Puri, SK Ind. J. Chem. 33B, p 251,1994; Vangapandu, S., Sachdeva, S., Jain, M, Singh, S., Singh , PP, Kaul, CL, Jain, R. Bioorg. Med. Chem. 2003, 11, 4557-4568).

Based on the procedure we reported for ring-substituted bioimidazoles (Jain, R., Cohen, LA King, MM, El-Kadi, N. Tetrahedron, 53, p2365, 1997, Tetrahedron, 53, p4539, 1997) Radical oxidative decarboxylation catalyzed by 8-nitroquinoline on silver of alkyl carboxylic acids with ammonium persulfate in 10% H ₂ SO ₄ as solvent is directly induced by a unique homolytic free radical. Resulting in simple ring alkylation, and mono and dialkylated 8-nitroquinolines are readily obtained in 60-65% yield. N ⁸ - (4-amino-1-methylbutyl) -2-alkyl-6-methoxy-8-quinoline derivatives ^{_{(1, R 3 = H)}} , N 8 - (4- amino-1-methylbutyl) -5- alkyl-6-methoxy-8-quinolinamine _{(1, R} 3 = H) and ^N 8 - (4-amino-1-methylbutyl) -2,5-dialkyl-6-methoxy-8-quinoline derivative (1, R ₃ = H) was synthesized in three steps from the appropriate 2-alkyl / 5-alkyl / 2,5-dialkyl-6-methoxy-8-nitroquinoline derivative according to the procedure reported earlier (Jain, R ., Jain, S., Gupta, RC, Anand, N., Dutta, GP and Puri, SK Ind. J. Chem. 33B, p 251, 1994; Vangapandu, S., Sachdeva, S., Jain, M, Singh, S., Singh, PP, Kaul, CL, Jain, R. Bioorg. Med. Chem. 2003, 11, 4557-4568).

Primaquine is known to have poor pharmacokinetic properties. Furthermore, the half-life of this drug is short (4-6 hours), its therapeutic index is low, it is highly toxic, and these are limiting factors for its use as an ideal drug. These limiting factors can be improved by a prodrug approach involving appropriate chemical modification of the drug. Prodrugs are pharmacologically inactive derivatives of a parent drug molecule that require natural or enzymatic conversion in the body to release active drugs that may have improved biological properties over the parent drug molecule. Indeed, binding of primaquine to small peptides has been shown to result in the formation of compounds that are less toxic and have a longer half-life than primaquine. In addition, the inventors have demonstrated early that it can be seen that the attachment of an amino acid to the side chain amino group at the C-8 position of the quinoline ring reduces toxicity and enhances biological activity (Jain, R., Jain, S., Gupta, RC, Anand, N., Dutta, GP and Puri, SK Ind. J. Chem. 33B, p 251, 1994; Hofsteenge, J., Capuano, A., Altszuler, R Moore, SJ Med. Chem. 29, p 1765, 1986, Philip, A., Kepler, JA, Johnson, BH, Carroll, FIJ Med. Chem. 31, p 870, 1988). Therefore, various amino acid derivatives of ring-substituted primaquine derivatives as their putative prodrugs were also synthesized. Therefore, when the 8-aminoquinoline compound (1, R ₃ = H) was reacted with Z- or Boc-protected amino acid in the presence of 1,3-dicyclohexylcarbodiimide (DCC) in anhydrous dichloromethane, quantitative yield was obtained. The protected compound was obtained. Removal of the protecting group either by catalytic hydrogenation in the presence of 10% Pd-C or by acid hydrolysis as in the case of the Boc group, in quantitative yield, yields the ring-substituted N ^1- [4- (6-Methoxy / 5-alkoxy-6-methoxy / -4-alkyl-8-quinolylamino) pentyl] -2-amino-2-substituted acetamide [1, R ₃ = various (R)-and (S)- Amino acid, L-unnatural amino acid] was obtained.

［式中、ＲはＨ、１〜８個の炭素原子を含む直鎖アルコキシ基、３〜７個の炭素原子を含む分枝鎖アルキル基、３〜１５個の炭素原子を含むシクロアルキル基、フェノキシ、および置換フェノキシ基を表し；Ｒ_１はＨ、ＣＨ_３およびＣ_２Ｈ_５を表し；Ｒ_２は１〜５個の炭素を含む直鎖アルキル基、分枝アルキル基、および３〜１５個の炭素原子を含むシクロアルキル基を表し、Ｒ_３は種々の（Ｒ）−および（Ｓ）−アミノ酸またはＬ−非天然アミノ酸を表す］
の環置換８−アミノキノリン類似体、およびその薬理学上許容される塩の製造方法であって、ここで、塩を形成する酸は本質的に有機であっても無機であってもよく、
ａ．８−ニトロキノリンとアルキルカルボン酸とを、非プロトン性溶媒中、硫酸、硝酸銀および過硫酸アンモニウムの存在下、還流温度にて５分〜１時間の範囲の時間反応させて、反応混合物から環置換８−アミノキノリンを単離すること；
ｂ．工程（ａ）で得られた環置換８−アミノキノリンと貴金属触媒および水素とを加圧下で反応させて環置換８−ニトロキノリンを得ること；
ｃ．環置換８−アミノキノリンと２−（４−ブロモペンチル）−１，３−イソインドリンジオンおよびトリエチルアミンとを、１００〜１４０℃の範囲の温度で３〜８時間の範囲の時間反応させてイソインドリンジオン誘導体を得ること；
ｄ．工程（ｃ）で得られたイソインドリンジオン誘導体とヒドラジン水和物とをアルコール系溶媒中で反応させて環置換Ｎ８−（４−アミノ−１−メチルブチル）−８−キノリンアミンを得ること；
ｅ．工程（ｄ）で得られたＮ８−（４−アミノ−１−メチルブチル）−８−キノリンアミンとＮ−保護アミノ酸およびジシクロヘキシルカルボジイミドとを、クロロアルカン溶媒中、１０〜５０℃の範囲の温度で反応させ、環置換保護アミノ酸キノリン誘導体を単離した後、その分子のアミノ酸部分を脱保護して式１の化合物を得ること
を含んでなる方法が提供される。 Thus, according to the present invention, the formula 1:

[Wherein R is H, a linear alkoxy group containing 1 to 8 carbon atoms, a branched alkyl group containing 3 to 7 carbon atoms, a cycloalkyl group containing 3 to 15 carbon atoms, Represents phenoxy and substituted phenoxy groups; R ₁ represents H, CH ₃ and C ₂ H ₅ ; R ₂ represents a linear alkyl group containing 1 to 5 carbons, a branched alkyl group, and 3 to 15 And R ₃ represents various (R)-and (S) -amino acids or L-unnatural amino acids]
Wherein the acid forming the salt may be organic or inorganic in nature, wherein the ring-forming 8-aminoquinoline analog and the pharmacologically acceptable salt thereof are:
a. 8-nitroquinoline and an alkyl carboxylic acid are reacted in an aprotic solvent in the presence of sulfuric acid, silver nitrate and ammonium persulfate at a reflux temperature for a time ranging from 5 minutes to 1 hour, and from the reaction mixture, ring substitution 8 Isolating aminoquinoline;
b. Reacting the ring-substituted 8-aminoquinoline obtained in step (a) with a noble metal catalyst and hydrogen under pressure to obtain a ring-substituted 8-nitroquinoline;
c. A ring-substituted 8-aminoquinoline is reacted with 2- (4-bromopentyl) -1,3-isoindolinedione and triethylamine at a temperature in the range of 100 to 140 ° C. for a time in the range of 3 to 8 hours to give isoindoline. Obtaining a dione derivative;
d. Reacting the isoindolinedione derivative obtained in step (c) with hydrazine hydrate in an alcohol solvent to obtain a ring-substituted N8- (4-amino-1-methylbutyl) -8-quinolinamine;
e. Reaction of N8- (4-amino-1-methylbutyl) -8-quinolinamine obtained in step (d) with N-protected amino acid and dicyclohexylcarbodiimide at a temperature in the range of 10 to 50 ° C. in a chloroalkane solvent. And isolating the ring-substituted protected amino acid quinoline derivative, followed by deprotecting the amino acid portion of the molecule to provide a compound of Formula 1 is provided.

  According to one embodiment of the present invention, the alkylcarboxylic acid is selected from the group consisting of trimethylacetic acid, isobutyric acid, cyclohexanecarboxylic acid, and 1-adamantanecarboxylic acid.

  According to another embodiment of the present invention, the 8-nitroquinoline is 6-methoxy-8-nitroquinoline, 5,6-dimethoxy-8-nitroquinoline, 4-ethyl-5-pentoxy-6-methoxy- Selected from 8-nitroquinoline, 4-ethyl-5-octoxy-6-methoxy-8-nitroquinoline, and 4-methyl-5,6-dimethoxy-8-nitroquinoline.

  According to another embodiment of the present invention, the catalyst used in the reduction step (b) is Raney nickel.

  According to another embodiment of the invention, the reduction is performed in a Parr hydrogenator at a pressure in the range of 40-50 psi.

  According to another embodiment of the invention, the alcohol solvent used is ethyl alcohol.

  According to another embodiment of the invention, the chloroalkane solvent is selected from dichloromethane.

  According to another embodiment of the invention, the deprotection of the benzyl ester of the amino acid part of the molecule in step (e) is carried out in the presence of Pd—C in methanol in the presence of hydrogen gas.

  According to another embodiment of the invention, deprotection of the t-Boc protected amino acid is performed in the presence of methanolic HCl.

  According to another embodiment of the invention, the compound of formula 1 is effective against P. berghei, P. yoelii infection in mice at doses ranging from 10-100 mg for 4 days.

According to another embodiment of the present invention, the compound LD ₅₀ of formula 1 exceeds 400 mg / kg body weight.

BRIEF DESCRIPTION OF THE TABLES Table 1: In vivo hematocidal activity of compounds against P. berghei infection in mice.
Table 2: In vivo hemocidal schizont activity of compounds against chloroquine and mefloquine drug resistant P. yoelii nigeriensis strains in mice.
Table 3: Acute toxicity study in Swiss mice (5, 50, 150, 450 mg / kg).
Table 4: Comparison of methemoglobin toxicity between conventional primaquine and 2-tert-butylprimaquine.
Table 5: In vitro antimalarial data of 2-tert-butylprimaquine against P. falciparum.

Biological activity Evaluation test procedure of blood schizont activity of potential antimalarial compounds against Plasmodium berghei (susceptible strain) and P. yoelii nigeriensis (resistant strain) infection in mice: Groups of 6 mice were inoculated intraperitoneally with infected red blood cells 1 × 10 ⁷ from donor mice. Four hours later, mice were orally administered test compound / chloroquine primaquine / vehicle. A total of 4 doses were given on day “0”, D + 1, D + 2 and D + 3. Blood smears were prepared on days D + 4 and D + 7, stained with Giemsa, and observed under a microscope. The minimum dose that completely suppressed parasitemia on days D + 4 and D + 7 was defined as “minimum effective dose (MED)” or “suppressed amount”, and the minimum amount that purified parasite blood by day 28 was “healing amount” It was. The results of the hemocidal schizont activity of the synthesized compounds are shown in Table 1.

As is evident from Table 1, the most effective compound of series 1 [R = R ₁ = R ₃ = H, R ₂ = (CH ₃ ) ₃ ] is cured at a dose of 10 mg / kg in a mouse model of P.berghei infection. This represents an advantage over chloroquine in this test model. On the other hand, the compounds (12-15, 17-18) were found to be curative at the initial test dose of 100 mg / kg in a P. berghei infected mouse model. Further screening of compounds (17-18) showed that they had inhibitory activity at 10 mg / kg in a P. berghei infected mouse model.

  Compound (1) which showed healing at 10 mg / kg against a P. berghei infected mouse model, then against chloroquine and mefloquine drug resistant P. yoelii nigeriensis (multi-drug resistant bacteria) at various doses in mice The results are summarized in Table 2.

The most effective compound 1 [R = R ₁ = R ₃ = H, R ₂ = (CH ₃ ) ₃ ] in this series was further evaluated for acute toxicity studies in Swiss mice. Groups of 10 mice with the same proportion of males and females received a single dose of 5, 50, 150 and 450 mg / kg. These compounds were evaluated for acute toxicity according to the protocol of Drug and Cosmetic Act, 1988, Govt. Of India, Ministry of Health and Family Welfare, schedule “Y” except for the number of animals used in this study. Indicates that the compound is quite safe at 50 mg / kg as shown in Table 3.

The obvious activity of 1 [R = R ₁ = R ₃ = H, R ₂ = (CH ₃ ) ₃ ] against chloroquine, mefloquine and quinine resistant strains P. yoelii nigeriensis makes this compound very attractive for clinical drug development It became a molecule. Since the basic substructure in our research is primaquine (a curative curative that is used clinically), we have an equivalent (to primaquine) or high degree of tissue killing schizont activity of this molecule I hope that. This unique mix of broad-range antimalarial activity against the blood, tissue, and resistant strains of human malaria parasites could make these compounds extremely attractive in malaria healing and prevention. Furthermore, the development of these compounds could provide the possibility of a single agent that can cure all recurrent and non-recurrent malaria.

Reduction of methemoglobin toxicity :
Methemoglobin toxicity studies were conducted on the most effective compounds. The protocol used is as follows: protocol reported earlier (Srivastava, P., Singh, S., Jain, GK, Puri, SK, Pandey, VC Ecotox. Environ. Safety. 2000, 45, 236 -239), the in vivo MetHb induction characteristics were evaluated with a rapid rodent animal model Mastomys coucha. In short, 6 individuals in each group between bisexual, 2-3 months of age, and body weight 40-50 g were used in this study. The drug was administered intraperitoneally (ip) or orally at various doses for 1 day / 3 consecutive days. Primaquin is used as the standard drug for the test. Primaquine is known to be readily absorbed from the gastrointestinal tract, reaching peak plasma concentrations within 3 hours and decreasing within an apparent half-life of 6 hours. With the above pharmacokinetic properties in mind, blood samples were collected 4 hours after drug administration and the% increase in MetHb was calculated.

The most effective analogs of this series Example ^43: N 8 - (4- amino-1-methylbutyl) -2-tert-butyl-6-methoxy-8-quinolinamine from methemoglobin toxicity made to Significant results are obtained. This 8-quinolinamine class of compounds, including primaquine, produces substantial amounts of methemoglobin (MetHb), which is one of the major toxic side effects of this type. The ^compound: - The Example 43 N 8 (4-amino-1-methylbutyl) -2-tert-butyl-6-methoxy-8-quinolinamine, 2-tert-butyl may also be referred to as PRIMA Kin] in There is no such toxic expression in vivo. This is a very important finding since it is the first effective 8-quinolinamine discovered to have no MetHb toxicity. “Comparison study using conventional standard drug (primaquine) regarding methemoglobin toxicity is shown in Table 4.

In vitro antimalarial activity against Plasmodium falciparum Protocol: Various drug dilutions [test compound and chloroquine (positive control)] were prepared in complete RPMI (RPMI 1640 medium + 10% AB ⁺ human serum; CRPMI). 50 μl of each dilution was transferred to individual wells of a microtiter plate in triplicate. Parasitic red blood cells (PE; mainly cyclic; 4% parasitemia; 5% hematocrit) were added to each well. The volume of each well was 200 μL with CRPMI. These plates were incubated at 37 ° C. in a candle jar. After 24-48 hours of incubation, thin-layer smears from each well were made and stained with Giemsa. The number of PE / 10,000 cells was counted. The percent inhibition by drug compared to the control (well without drug) was plotted against the individual log concentration of drug. Next, the IC _{50 of the} test compound was calculated using non-linear regression analysis.

The following examples are given by way of illustration and are not intended to limit the scope of the invention.
Example 1
Synthesis of 2-tert-butyl-6-methoxy-8-nitroquinoline 6-methoxy-8-nitroquinoline (1 mmol) (Scheme 1) was dissolved in CH ₃ CN (5 mL) while warming the reaction mixture to 70 ° C. did. Next, silver nitrate (0.6 mmol), trimethylacetic acid (2.5 mmol), and 10% H ₂ SO ₄ (10 mL) were added to the reaction mixture. A solution of ammonium persulfate (3 mmol) in freshly prepared water (10 mL) was added dropwise over 10 minutes to this pre-heated (70 ° C.) mixture. The heat source was then removed and the reaction proceeded with the evolution of carbon dioxide. After 10 minutes, the reaction mixture was poured onto ice and the resulting mixture was made alkaline by adding 30% NH ₄ OH. Extracted with ethyl acetate (4 × 50 mL) and the combined extracts were washed with NaCl solution (2 × 10 mL). It was dried over Na ₂ SO _4, to give an oil and the solvent removed under vacuum, which was subjected to flash column chromatography on silica gel (230-400 mesh), 2-tert-butyl-6-methoxy -8 -Nitroquinoline was obtained in good yield.
Yield: 62%; IR (KBr): 1529 and 1362 cm ^-1 (NO ₂ ); ¹ H NMR (CDCl ₃ ): δ 8.03 (d, 1H, 4-Ar-H, J = 8.7 Hz), 7.62 (d, 1H, 3-Ar-H, J = 2.7 Hz) 7.58 (d, 1H, 7-Ar-H, J = 8.8 Hz), 7.23 (d, 1H, 5-Ar-H, J = 2.5 Hz ), 3.96 (s, 3H, OCH ₃ ), 1.41 (s, 9H, 3 x CH ₃ ) ¹³ C NMR (CDCl ₃ ): δ 155.5, 134.65, 128.10, 120.2, 115.4, 109.1, 56.1, 38.3, 29.8; MS (EI): m / z 260 (M ⁺ ).

  The examples listed below are prepared by reacting 5,6-dimethoxy-8-nitroquinoline with trimethylacetic acid, cyclohexanecarboxylic acid and isobutyric acid, respectively, using the protocol described above.

Example 2
2-tert-butyl-5,6-dimethoxy-8-nitro-quinoline <br/> Yield: 65%; IR (KBr) : 1528 cm -1 and _{^{1349 cm -1 (NO 2);}} 1 H NMR (CDCl ₃ ): δ 8.05 (d, 1H, 4-Ar-H, J = 9 Hz), 7.89 (s, 1H, 7-Ar-H), 7.60 (d, 1H, 3-Ar-H, J = 9 Hz), 4.07 (s, 3H, 5-OCH ₃ ), 4.02 (s, 3H, 6-OCH ₃ ), 1.42 (s, 9H, 3xCH ₃ ); HRMS (ESI): 291.2 (M + 1).

Example 3
2-cyclohexyl-5,6-dimethoxy-8-nitro-quinoline <br/> Yield: 57%; IR (KBr) : 1540 and _{^{1375 cm -1 (NO 2);}} 1 H NMR (CDCl 3): δ 7.94 (d, 1H, 4-Ar-H, J = 9 Hz), 7.75 (s, 1H, 7-Ar-H), 6.93 (d, 1H, 3-Ar-H, .J = 9.Hz), 3.98 (s, 3H, 5-OCH ₃ ), 3.97 (s, 3H, 6-OCH ₃ ), 2.92 (m, 1H, CH), 1.25 (s, 10H, 5xCH ₂ ); MS (EI): m / z 316 (M ⁺ ).

Example 4
2-isopropyl-5,6-dimethoxy-8-nitro-quinoline <br/> Yield: 55%; IR (KBr) : 1565 and _{^{1340 cm -1 (NO 2);}} 1 H NMR (CDCl 3): δ 7.87 (dd, 1H, 4-Ar-H, J = 8.9 Hz), 7.65 (s, 1H, 7-Ar-H), 6.86 (d, 1H, 3-Ar-H, J = 8.9 Hz), 4.08 ( s, 3H, 5-OCH ₃ ), 4.02 (s, 3H, 6-OCH ₃ ), 3.12 (m, 1H, CH), 1.25 (s, 6H, 2xCH ₃ ), MS (EI): m / z 276 (M ⁺ ).

Example 5
2-tert-Butyl-4-ethyl-5-pentoxy-6-methoxy-8-nitroquinoline This compound was prepared according to the above procedure and 4-ethyl-5-pentoxy-6-methoxy-8-nitroquinoline as starting material. Was synthesized in the presence of trimethylacetic acid.
Yield: 42%; IR (KBr): 1550, 1345 cm ^-1 (NO ₂ ); ¹ H NMR (CDCl ₃ ): δ 7.47 (s, 1H, 7-Ar-H), 7.18 (s, 1H, 3-Ar-H), 4.03 (t, 2H, OCH ₂ ), 3.90 (s, 3H, OCH ₃ ), 3.18 (q, 2H, CH ₂ ), 1.80 (m, 4H, 2xCH ₂ ), 1.33 (m , 2H, CH ₂ ), 1.32 (s, 3H, 3xCH ₃ ), 0.82 (t, 3H, CH ₃ ); MS (APCI): m / z 375 (M + 1).

Example 6
2-tert-Butyl-4-ethyl-5-octoxy-6-methoxy-8-nitroquinoline This compound was prepared according to the above procedure and 4-ethyl-5-octoxy-6-methoxy-8-nitroquinoline as starting material. Was synthesized in the presence of trimethylacetic acid.
Yield: 35%; IR (KBr): 1522 and 1345 cm ^-1 (NO ₂ ); ¹ H NMR (CDCl ₃ ): δ 7.75 (s, 1H, 7-Ar-H), 7.33 (s, 1H, 3-Ar-H), 4.10 (t, 2H, OCH ₂ ), 3.98 (s, 3H, OCH ₃ ), 3.25 (q, 2H, CH ₂ ), 1.64 (m, 2H, CH ₂ ), 1.52 (m , 6H, 3xCH ₂ ), 1.31 (s, 9H, 3xCH ₃ ), 0.88 (t, 3H, CH ₃ ); MS (APCI): m / z 417 (M + 1).

Example 7
2-tert-Butyl-4-methyl-5,6-dimethoxy-8-nitroquinoline This compound was prepared by combining the above procedure with 4-methyl-5,6-dimethoxy-8-nitroquinoline as starting material and trimethylacetic acid. Synthesized using in the presence.
Yield: 45%; IR (KBr): 1525 and 1340 cm ^-1 (NO ₂ ); ¹ H NMR (CDCl ₃ ): δ 7.74 (s, 1H, 7-Ar-H), 7.29 (s, 1H, 3-Ar-H), 4.00 (s, 3H, 5-OCH ₃ ), 3.96 (s, 3H, 6-OCH ₃ ), 2.87 (s, 3H, CH ₃ ), 1.38 (s, 9H, 3xCH ₃ ) , MS (APCI): m / z 305 (M + 1).

Example 8
Synthesis of 2-adamantyl-6-methoxy-8-nitroquinoline 6-methoxy-8-nitroquinoline (1 mmol) (Scheme 1) was dissolved in CH ₃ CN (5 mL) while the reaction mixture was warmed to 70 ° C. Next, silver nitrate (0.6 mmol), 1-adamantanecarboxylic acid (2 mmol), and 10% H ₂ SO ₄ (10 mL) were added to the reaction mixture. A solution of ammonium persulfate (3 mmol) in freshly prepared water (10 mL) was added dropwise over 10 minutes to this pre-heated (70 ° C.) mixture. The heat source was then removed and the reaction proceeded with the evolution of carbon dioxide. After 10 minutes, the reaction mixture was poured onto ice and the resulting mixture was made alkaline by adding 30% NH ₄ OH. Extracted with ethyl acetate (4 × 50 mL) and the combined extracts were washed with NaCl solution (2 × 10 mL). It was dried over Na ₂ SO _4, to give an oil and the solvent removed under vacuum, which was subjected to flash column chromatography on silica gel (230-400 mesh), 2-adamantyl-6-methoxy-8-nitro Quinoline was obtained in good yield.
Yield: 70%; IR (Br): 1527 cm ^-1 (NO ₂ ); ¹ H NMR (CDCl ₃ ): δ 8.04 (d, 1H, 4-Ar-H, J = 8.7 Hz), 7.61 (d , 1H, 7-Ar-H, J = 2.2 Hz), 7.56 (d, 1H, 3-Ar-H, J = 8.7 Hz), 7.23 (d, 1H, 5-Ar-H, J = 2.4 Hz) , 3.95 (s, 3H, OCH ₃ ), 2.12 (m, 15H, 12xCH ₂ and CH); ¹³ C NMR (CDCl ₃ ): δ 168.92, 155.49, 134.58, 128.19, 119.84, 115.31, 109.04, 56.11, 41.57, 39.97, 36.74, 28.67; HRMS (ESI): 339 (M + 1).

Synthesis of 5-cyclopentyl-6-methoxy-8-nitroquinoline and 2,5-dicyclopentyl-6-methoxy-8-nitroquinoline 6-methoxy-8-nitroquinoline (1 mmol) (Scheme 1) was added to the reaction mixture. Dissolved in CH ₃ CN (5 mL) while warming to 70 ° C. Next, silver nitrate (0.6 mmol), 1-adamantanecarboxylic acid (2.5 mmol), and 10% H ₂ SO ₄ (10 mL) were added to the reaction mixture. A solution of ammonium persulfate (3 mmol) in freshly prepared water (10 mL) was added dropwise over 10 minutes to this pre-heated (70 ° C.) mixture. The heat source was then removed and the reaction proceeded with the evolution of carbon dioxide. After 10 minutes, the reaction mixture was poured onto ice and the resulting mixture was made alkaline by adding 30% NH ₄ OH. Extracted with ethyl acetate (4 × 50 mL) and the combined extracts were washed with NaCl solution (2 × 10 mL). Drying over Na ₂ SO ₄ and removal of the solvent under vacuum gave a mixture of mono and dicyclopentyl derivatives, which were separated by flash column chromatography on silica gel (230-400 mesh) to give 5-cyclopentyl-6 -Methoxy-8-nitroquinoline and 2,5-dicyclopentyl-6-methoxy-8-nitroquinoline were obtained.

Example 9
5-cyclopentyl-6-methoxy-8-nitroquinoline <br/> Yield: 52%; IR (KBr) : 1535 and _{^{1215 cm -1 (NO 2);}} 1 H NMR (CDCl 3): δ 8.82 (d , 1H, 2-Ar-H, J = 4.1 Hz), 8.06 (d, 1H, 4-Ar-H, J = 8.3 Hz), 7.42 (m, 1H, 3-Ar-H), 7.14 (s, 1H, 7-Ar-H), 3.98 (s, 3H, OCH ₃ ), 3.15 (m, 1H, CH), 1.64 (m. 8H, 4xCH ₂ ) MS (EI): m / z 272 (M ⁺ ) .

Example 10
2,5-dicyclopentyl-6-methoxy-8-nitroquinoline <br/> Yield: 10%; IR (KBr) : 1545, 1388 cm -1 (NO 2); 1 H NMR (CDCl 3): δ 8.09 (d, 1H, 4-Ar-H, J = 8 Hz), 7.47 (d, 1H, 3-Ar-H, J = 8 Hz), 7.17 (s, 1H, 7-Ar-H), 3.98 (s, 3H, OCH ₃ ), 2.82 (m, 2H, 2xCH), 1.74 (m, 16H, 8xCH ₂ ); MS (EI): m / z 340 (M ⁺ ).
The examples listed below are prepared by reacting 6-methoxy-8-nitroquinoline with isobutyric acid and cyclohexanecarboxylic acid, respectively, using the protocol described above.

Example 11
5-isopropyl-6-methoxy-8-nitroquinoline <br/> Yield: 47%; IR (KBr) : 1540 and _{^{1388 cm -1 (NO 2);}} 1 H NMR (CDCl 3): δ 8.79 (d , 1H, 2-Ar-H, J = 4.1 Hz), 8.07 (d, 1H, 4-Ar-H, J = 8.2 Hz), 7.4 (dd, 1H, 3-Ar-H, J = 8.2 Hz) , 7.14 (s, 1H, 7-Ar-H), 3.95 (s, 3H, OCH ₃ ), 3.19 (m, 1H, CH), 1.43 (d, 6H, 2xCH ₃ ); ¹³ C NMR (CDCl ₃ ) : δ 156.97, 149.81, 134.32, 132.13, 128.01, 122.74, 118.86, 106.61, 56.27, 30.19, 20.69; MS (EI): m / z 246 (M ⁺ ).

Example 12
2,5-diisopropyl-6-methoxy-8-nitroquinoline <br/> Yield: 12%; IR (KBr) : 1545 and _{^{1395 cm -1 (NO 2);}} 1 H NMR (CDCl 3): δ 8.09 (d, 1H, 4-Ar-H, J = 8.4 Hz), 7.47 (d, 1H, 3-Ar-H, .J = 8 Hz), 7.19 (s, 1H, 7-Ar-H), 3.99 (s, 3H, OCH ₃ ), 3.22 (m, 1H, 2xCH), 1.52 (d, 6H, 2xCH ₃ ), 1.48 (d, 6H, 2xCH ₃ ); MS (El): m / z 288 (M ⁺ ).

Example 13
5-cyclohexyl-6-methoxy-8-nitroquinoline <br/> Yield: 43%; IR (KBr) : 1533 and _{^{1386 cm -1 (NO 2);}} 1 H NMR (CDCl 3): δ 8.79 (d , 1H, 2-Ar-H, J = 4 Hz), 8.05 (d, 1H, 4-Ar-H, J = 8.3 Hz), 7.43 (dd, 1H, 3-Ar-H, J = 8.2 Hz) , 7.13 (s, 1H, 7-Ar-H), 3.99 (s, 3H, OCH ₃ ), 2.82 (m, 1H, CH), 1.67 (m, 10H, 5xCH ₂ ); ¹³ C NMR (CDCl ₃ ) : δ 156.37, 128.76, 127.54, 122.29, 106.23, 71.72, 55.87, 40.69, 29.63, 27.65, 26.71, 25.73, 19.09; MS (EI): m / z 286 (M ⁺ ).

Example 14
2,5-dicyclohexyl-6-methoxy-8-nitroquinoline <br/> Yield: 11%; IR (KBr) : 1537 and _{^{1382 cm -1 (NO 2);}} 1 H NMR (CDCl 3): δ 8.09 (d, 1H, 4-Ar-H, J = 8.2 Hz), 7.49 (d, 1H, 3-Ar-H, J = 8.2 Hz), 7.12 (s, 1H, 7-Ar-H), 3.94 ( s, 3H, OCH ₃ ), 2.87 (m, 1H, 2xCH), 1.77 (m, 20H, 10xCH ₂ ); MS (EI): m / z 368 (M ⁺ ).

General Method for the Synthesis of Ring-Substituted 8-Quinolinamine A solution of ring-substituted 8-nitroquinoline (5 mmol) in 95% ethanol (20 mL) was about ran over Raney nickel (T ₁ grade) in a Parr hydrogenator. Hydrogenated at 45 psi for 6 hours. The catalyst was removed by filtration and the solvent was removed under reduced pressure to give the ring-substituted 8-quinolinamine as an oil that was subjected to the next reaction step without further purification.

Example 15
2-tert-butyl-6-methoxy-8-quinolinamine <br/> Yield: 86%; IR (KBr) : 3480 and _{^{3375 cm -1 (NH 2);}} 1 H NMR (CDCl 3): δ 7.84 (d, 1H, 4-Ar-H; J = 8.6 Hz), 7.41 (d, 1H, 3-Ar-H, J = 8.6 Hz), 6.54 (d, 1H, 7-Ar-H, J = 2.5 Hz), 6.43 (d, 1H, 5-Ar-H, J = 2.5 Hz), 4.98 (bs, 1H, NH ₂ ), 3.83 (s, 3H, OCH ₃ ), 1.42 (s, 9H, 3xCH ₃ ) ; HRMS (ESI): m / z 231 (M + 1).

Example 16
2-adamantyl-6-methoxy-8-quinolinamine <br/> Yield: 94%; IR (KBr) : 3445-3353 cm -1 (NH 2); 1 H NMR (CDCl 3): δ 7.89 (d , 1H, 4-Ar-H, J = 8.6 Hz), 7.41 (d, 1H, 3-Ar-H, J = 8.6 Hz), 6.55 (d, 1H, 7-Ar-H, J = 2.2 Hz) , 6.45 (s, 1H, 5-Ar-H, J = 2.1 Hz), 5.21 (bs, 2H, NH ₂ ), 3.75 (s, 1H, OCH ₃ ) 2.29-1.75 (m, 15H, 12xCH ₂ and CH ); ¹³ C NMR (CDCl ₃ ): δ 163.30, 158.85, 145.86, 134.90, 130.89, 128.82, 118.38, 96.27, 91.65, 55.19, 42.10, 39.30, 37.81, 36.94, 31.94, 29.71, 28.89, 22.71, 14.64, 14.16 ; HRMS (APCI): m / z 309 (M + 1).

Example 17
5-cyclopentyl-6-methoxy-8-quinolinamine <br/> Yield: 92%; IR (KBr) : 2958 and _{^{2928 cm -1 (NH 2);}} 1 H NMR (CDCl 3): δ 8.58 (d , 1H, 2-Ar-H), 7.90 (d, 1H, 4-Ar-H), 7.26 (s, 1H, 3-Ar-H), 6.51 (s, 1H, 7-Ar-H), 5.09 (bs, 2H, NH ₂ ), 3.89 (s, 3H, OCH ₃ ), 3.57 (m, 1H, CH) 1.88 (m, 8H, 4xCH ₂ ); MS (EI): m / z 242 (M ⁺ ) .

Example 18
5-isopropyl-6-methoxy-8-quinolinamine <br/> Yield: 95%; IR (KBr) : 3330 cm -1 (NH 2); 1 H NMR (CDCl 3): δ 7.71 (d, 1H , 2-Ar-H), 7.54 (d, 1H, 4-Ar-H), 6.76 (1H, d, 3-Ar-H), 6.53 (s, 1H, 7-Ar-H), 5.13 (bs , 2H, NH ₂ ), 4.22 (s, 3H, OCH ₃ ), 3.07 (m, 1H, CH), 1.39 (d, 6H, 2xCH ₃ ); MS (EI): m / z 216 (M ⁺ ).

Example 19
5-cyclohexyl-6-methoxy-8-quinolinamine <br/> Yield: 82%; IR (KBr) : 3008 and _{^{2926 cm -1 (NH 2);}} 1 H NMR (CDCl 3): δ 8.59 (d , 1H, 2-Ar-H, J = 4 Hz), 7.92 (d, 1H, 4-Ar-H, J = 8.4 Hz), 7.26 (d, 1H, 3-Ar-H, J = 8.2 Hz) , 6.50 (s, 1H, 7-Ar-H), 5.1 (bs, 2H, NH ₂ ), 3.89 (s, 3H, CH ₃ O) 3.10 (m, 1H, CH), 1.69 (m, 10H, 5xCH ₂ ); MS (EI): m / z 256 (M ⁺ ).

Example 20
2,5 dicyclopentyl-6-methoxy-8-quinolinamine <br/> Yield: 90%; IR (KBr) : 2930 cm -1 (NH 2); 1 H NMR (CDCl 3): δ 7.92 ( d, 1H, 4-Ar-H), 7.23 (s, 1H, 3-Ar-H), 6.57 (s, 1H, 7-Ar-H), 5.09 (bs, 2H, NH ₂ ), 3.89 (s , 3H, OCH3), 3.29 (m, 1H, 2xCH) 1.94 (m, 16H, 8xCH ₂ ); MS (EI): m / z 310 (M ⁺ ).

Example 21
2,5-diisopropyl-6-methoxy-8-quinolinamine <br/> Yield: 88%; IR (KBr) : 3333 cm -1 (NH 2); 1 H NMR (CDCl 3): δ 7.67 (d , 1H, 4-Ar-H), 6.90 (1H, d, 3-Ar-H), 6.77 (s, 1H, 7-Ar-H), 5.17 (bs, 2H, NH ₂ ), 4.15 (s, 3H, OCH ₃ ), 3.17 (m, 2H, 2xCH), 1.42 (d, 6H, 2xCH ₃ ), 1.37 (d, 6H, 2xCH ₃ ); MS (EI): m / z 258 (M ⁺ ).

Example 22
2,5-dicyclohexyl-6-methoxy-8-quinolinamine <br/> Yield: 88%; IR (KBr) : 3030 cm -1 (NH 2); 1 H NMR (CDCl 3): δ 7.95 (d , 1H, 4-Ar-H), 7.28 (d, 1H, 3-Ar-H), 6.58 (s, 1H, 7-Ar-H), 5.14 (bs, 2H, NH ₂ ), 3.84 (s, 3H, OCH ₃ ) 3.23 (m, 2H, 2xCH), 1.77 (m, 20H, 10xCH ₂ ); MS (EI): m / z 338 (M ⁺ ).

Example 23
2-tert-butyl-5,6-dimethoxy-8-quinolinamine <br/> Yield: 100%; IR (KBr) : 3461 cm -1 (NH 2); 1 H NMR (CDCl 3): δ 8.32 (d, 1H, 4-Ar-H, J = 9 Hz), 7.52 (d, 1H, 3-Ar-H, J = 9 Hz), 6.81 (s, 1H, 7-Ar-H), 5.1 ( bs, 2H, NH ₂ ), 3.95 (s, 3H, 5-OCH ₃ ), 3.88 (s, 3H, 6-OCH ₃ ) 1.51 (s, 9H, 3xCH ₃ ); HRMS (ESI): 261.2 (M + 1).

Example 24
2-cyclohexyl-5,6-dimethoxy-8-quinolinamine <br/> Yield: 80%; IR (KBr) : 3230 cm -1 (NH 2); 1 H NMR (CDCl 3): δ 8.33 (d , 1H, 4-Ar-H, J = 9.4 Hz), 7.51 (d, 1H, 7-Ar-H, J = 9.5 Hz), 6.81 (s, 1H, 7-Ar-H), 5.17 (bs, 2H, NH ₂ , D ₂ O), 3.95 (s, 3H, 5-OCH ₃ ), 3.88 (s, 3H, 6-OCH ₃ ), 3.1 (m, 1H, CH), 1.45 (m, 10H, 5xCH ₂ ); MS (EI): m / z 286 (M ⁺ ).

Example 25
2-isopropyl-5,6-dimethoxy-8-quinolinamine <br/> Yield: 100%; IR (KBr) : 3355 cm -1 (NH 2); 1 H NMR (CDCl 3): δ 7.70 (d , 1H, 4-Ar-H), 7.23 (d, 1H, 3-Ar-H), 6.82 (s, lH, 7-Ar-H), 5.71 (bs, 2H, NH ₂ ), 4.14 (s, 3H, 5-OCH ₃ ), 4.12 (s, 3H, 6-OCH ₃ ), 3.1 (m, 1H, CH), 1.2 (s, 6H, 2CH ₃ x); MS (El): m / z 246 ( M ⁺ ).

Example 26
2-tert-butyl-4-ethyl-5-pentoxy-6-methoxy-8-quinolinamine <br/> Yield: 95%; IR (KBr) : 3350 cm -1 (NH 2); 1 H NMR ( CDCl ₃ ): δ 7.28 (s, 1H, 3-Ar-H), 6.92 (s, 1H, 7-Ar-H), 4.06 (t, 2H, OCH ₂ ), 3.93 (s, 3H, OCH3), 3.27 (q, 2H, CH ₂ ), 1.85 (m, 4H, 2xCH ₂ ), 1.39 (m, 2H, CH ₂ ), 1.40 (s, 3H, 3xCH ₃ ), 0.94 (t, 3H, CH ₃ ); MS (APCI): m / z 345 (M + 1).

Example 27
2-tert-butyl-4-ethyl-5-octoxy-6-methoxy-8-quinolinamine <br/> Yield: 93%;%; IR ( KBr): 3355 cm -1 (NH 2); 1 H NMR (CDCl ₃ ): δ 7.33 (s, 1H, 3-Ar-H), 6.97 (s, 1H, 7-Ar-H), 4.1 (t, 2H, OCH ₂ ), 3.97 (s, 3H, OCH ₃ ), 3.29 (q, 2H, CH ₂ ), 1.67 (m, 2H, CH ₂ ), 1.57 (m, 6H, 3xCH ₂ ), 1.41 (s, 9H, 3CH ₃ x), 0.98 (t, 3H, CH3); MS (APCI): m / z 375 (M + 1)

Example 28
2-tert-butyl-4-methyl-5,6-dimethoxy-8-quinolinamine <br/> Yield: 90%; IR (KBr) : 3358 cm -1 (NH 2); 1 H NMR (CDCl 3 ): δ 7.39 (s, 1H, 3-Ar-H), 6.99 (s, 1H, 7-Ar-H), 4.00 (s, 3H, 5-OCH ₃ ), 3.96 (s, 3H, 6-OCH ₃ ), 2.89 (s, 3H, CH ₃ ), 1.42 (s, 9H, 3xCH ₃ ), MS (APCI): m / z 275 (M + 1).

General method for the synthesis of ring-substituted 2- [4- (6-methoxy-8-quinolineamino) pentyl] -1,3-isoindolinedione Ring-substituted 8-quinolinamine (6 mmol), 2- (4-bromo A mixture of pentyl) -1,3-isoindolinedione (6.0 mmol) and triethylamine (6 mmol) was heated at 120 ° C. with stirring for 3 hours. An additional amount of 2- (4-bromopentyl) -1,3-isoindolinedione (6 mmol) and triethylamine (6 mmol) was added and stirring was continued for 4 hours while heating. A third equivalent of 2- (4-bromopentyl) -1,3-isoindolinedione (6 mmol) and triethylamine (6 mmol) was added and the reaction mixture was heated at 120 ° C. for 16 hours. The reaction mixture was then diluted with ethyl acetate (100 mL) and filtered. The filtrate was basified with 2N NaOH solution and extracted with ethyl acetate (3 × 50 mL). The combined extracts were washed with water (2 × 10 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure to give a dark residue that was purified on silica gel (ethyl acetate / hexanes as eluent). 230-400 mesh) to give a ring-substituted 2- [4- (6-methoxy-8-quinolineamino) pentyl] -1,3-isoindoline-dione.

Example 29
2- [4- (2-tert-butyl-6-methoxy-8-quinolineamino) pentyl] -1,3-isoindolinedione Yield: 83%; IR (KBr): 3387 cm ^-1 (NH ₂ ), 1713 (C = 0); ¹ H NMR (CDCl ₃ ): δ 7.83 (d, 1H, 4-Ar-H; J = 8.5 Hz), 7.80 (m, 4H, Ar-H), 7.41 (d, 1H, 3-Ar-H, J = 8.5 Hz), 6.27 (d, 1H, 7-Ar-H, J = 2.43 Hz), 6.24 (d, 1H, 5-Ar-H, J = 2.4 Hz), 6.13 (bs, 1H, NH), 3.75 (t, 2H, N-CH ₂ ), 3.62 (bs, 1H, N-CH), 1.86-1.61 (m, 4H, 2xCH ₂ ), 1.41 ( s, 9H, 3xCH ₃ ), 1.29 (d, 3H, CH ₃ ); ¹³ C NMR (CDCl ₃ ): δ 168.39, 163.33, 158.81, 144.71, 134.97, 133.98, 133.50, 132.11, 132.07, 127.27, 123.16, 118.77 , 96.75, 91.64, 55.18, 50.53, 47.99, 38.07, 37.97, 37.68, 37.17, 33.98, 30.25, 27.02, 26.46, 25.31, 20.59; MS (EI): m / z 445 (M ⁺ ).

Example 30
2- [4- (5-Cyclopentyl-6-methoxy-8-quinylamino) pentyl] -1,3-isoindolinedione Yield: 44%; IR (KBr): 1712 cm < ^-1 > (C = O); ¹ H NMR (CDCl ₃ ): δ 8.56 (d, 1H, 2-Ar-H, J = 2.8 Hz), 7.81 (m, 4H, Ar-H), 7.91 (d, 1H, 4-Ar -H, J = 7.8 Hz), 7.21 (m, 1H, 3-Ar-H), 6.65 (s, 1H, 7-Ar-H), 5.12 (bs, 1H, NH), 3.89 (s, 3H, OCH ₃ ), 3.69 (m, 3H, N-CH and N-CH ₂ ) 3.46 (m, 1H, CH), 2.02 (m, 4H, 2xCH ₂ ), 1.69 (m, 8H, 4xCH ₂ ), 1.22 ( d, 3H, CH ₃ ); MS (EI): m / z 457 (M ⁺ ).

Example 31
2- [4- (2-adamantyl-6-methoxy-8-quinolylamino) pentyl] -1,3-isoindolinedione Yield: 56%; IR (KBr): 3363 cm ^-1 (NH) , 1711 cm ^-1 (C = O); ¹ H NMR (CDCl ₃ ): δ 7.86 (d, 1H, 4-Ar-H), 7.81 (m, 4H, Ar-H), 7.38 (d, 1H, 3-Ar-H, J = 8.4 Hz), 6.27 (d, 1H, 7-Ar-H), 6.25 (d, 1H, 5-Ar-H), 3.85 (s, 3H, OCH ₃ ), 3.69 ( m, 3H, N-CH and N-CH ₂ ) 1.91 (m, 15H, 12xCH ₂ and CH), 1.6 (m, 4H, 2xCH ₂ ), 1.31 (d, 3H, CH ₃ ); ¹³ C NMR (CDCl ₃ ): δ 168.39, 163.18, 158.78, 144.97, 134.85, 133.91, 127.58, 123.16, 118.39, 96.51, 91.54, 69.48, 55.17, 47.89, 42.05, 39.29, 38.79, 38.01, 37.82, 36.94, 34.001, 33.17, 28.001, 33.17 27.98, 25.31, 24.60, 20.66, 19.93; HRMS (APCI): 524 (M + 1).

Example 32
2- [4- (5-Isopropyl-6-methoxy-8-quinolylamino) pentyl] -1,3-isoindolinedione Yield: 53%; IR (KBr): 3433 cm ^-1 (NH) , 1709 cm ^-1 (C = O); ¹ H NMR (CDCl ₃ ): δ 8.57 (d,
1H, 2-Ar-H, J = 3.0 Hz), 8.10 (d, 1H, 4-Ar-H, J = 7.9 Hz), 7.83 (m, 4H, Ar-H), 7.37 (dd, 1H, 3 -Ar-H, J = 8.0 Hz), 6.84 (s, 1H, 7-Ar-H), 4.81 (bs, 1H, NH), 3.86 (s, 3H, OCH ₃ ) 3.52 (m, 3H, N- CH and N-CH ₂ ), 1.70 (m, 2H, CH ₂ ), 1.46 (m, 2H, CH ₂ ), 1.32 (d, 6H, 2xCH ₃ ), 0.98 (d, 3H, CH ₃ ); ¹³ C NMR (CDCl ₃ ): 167.76, 158.49, 145.49, 143.41, 138.41, 138.43, 134.47, 134.21, 131.26, 127.27, 127.05, 122.87, 121.08, 98.27, 54.41, 37.06, 34.06, 34.51, 27.86, 23.90, 20.55; MS ( El): m / z 431 (M ⁺ ).

Example 33
2- [4- (5-cyclohexyl-6-methoxy-8-quinylamino) pentyl] -1,3-isoindolinedione Yield: 63%; IR (KBr): 3387 cm- ¹ (NH) , 1713 cm ^-1 (C = O); ¹ H NMR (CDCl ₃ ): δ 8.57 (d, 1H, 2-Ar-H), 7.84 (m, 4H, Ar-H), 7.81 (d, 1H, 4-Ar-H, J = 6 Hz), 7.26 (d, 1H, 3-Ar-H, J = 6 Hz), 6.64 (s, 1H, 7-Ar-H), 3.89 (s, 3H, OCH ₃ ), 3.68 (t, 2H, N-CH ₂ ) 3.32 (m, 1H, N-CH), 3.18 (m, 1H, CH), 2.22 (m, 4H, 2xCH ₂ ), 1.5 (m, 10H, 5xCH ₂ ), 1.1 (d, 3H, CH ₃ ); MS (EI): m / z 501 (M ⁺ ).

Example 34
2- [4- (2,5-dicyclopentyl-6-methoxy-8-quinylamino) pentyl] -1,3-isoindolinedione Yield: 89%; IR (KBr): 1715 cm ^-1 (C = O); ¹ H NMR (CDCl ₃ ): δ 7.95 (d, 1H, 4-Ar-H, J = 7.9 Hz), 7.85 (m, 4H, Ar-H), 7.27 (d, 1H, 3-Ar-H), 6.69 (s, 1H, 7-Ar-H), 5.12 (bs, 1H, NH), 3.89 (s, 3H, OCH ₃ ), 3.65 (m, 3H, N-CH and NCH _2- ) 3.44 (m, 2H, 2xCH), 2.07 (m, 4H, 2xCH2), 1.62 (m, 16H, 8xCH ₂ ), 1.21 (d, 3H, CH ₃ ); MS (EI): m / z 525 (M ⁺ ).

Example 35
2- [4- (2,5-diisopropyl-6-methoxy-8-quinolylamino) pentyl] -1,3-isoindolinedione Yield: 77%; IR (KBr): 3400 cm ^-1 ( NH), 1715 cm ^-1 (C = O); ¹ H NMR (CDCl ₃ ): δ 8.12 (d, 1H, 4-Ar-H), 7.80 (m, 4H, Ar-H), 7.35 (d, 1H, 3-Ar-H), 6.87 (s, 1H, 7-Ar-H), 4.82 (bs, 1H, NH), 3.87 (s, 3H, OCH ₃ ) 3.53 (m, 3H, N-CH and N-CH ₂ ), 3.10 (m, 2H, 2xCH), 1.73 (m, 2H, CH ₂ ), 1.49 (m, 2H, CH ₂ ), 1.39 (d, 6H, 2xCH ₃ ), 1.32 (d, 6H , 2xCH ₃ ), 0.98 (d, 3H, CH ₃ ); MS (El): m / z 473 (M ⁺ ).

Example 36
2- [4- (2,5-dicyclohexyl-6-methoxy-8-quinylamino) pentyl] -1,3-isoindolinedione Yield: 88%; IR (KBr): 3360 cm ^-1 ( NH), 1713 cm ^-1 (C = O); ¹ H NMR (CDCl ₃ ): δ 7.88 (d, 1H, 4-Ar-H), 7.23 (d, 1H, 3-Ar-H), 6.67 ( s, 1H, 7-Ar-H), 3.88 (s, 3H, OCH ₃ ), 3.65 (t, 2H, N-CH ₂ ) 3.33 (m, 1H, N-CH), 3.15 (m, 2H, 2xCH ), 2.22 (m, 4H, 2xCH ₂ ), 1.65 (m, 20H, 10xCH ₂ ), 1.17 (d, 3H, CH ₃ ); MS (El): m / z 553.

Example 37
2- [4- (2-tert- butyl-5,6-dimethoxy-8-Kinoriruamino) pentyl] -1,3-isoindoline dione <br/> Yield: 56.4%; IR (KBr) : 3382 cm - ¹ (NH), 1712 cm ^-1 (C = O); ¹ H NMR (CDCl ₃ ): δ 8.20 (d, 1H, 4-Ar-H, J = 9 Hz), 7.82 (m, 4H, Ar- H), 7.46 (d, 1H, 3-Ar-H, J = 9 Hz), 6.38 (s, 1H, 7-Ar-H), 6.02 (bs, 1H, NH), 3.96 (s, 3H, 5 -OCH ₃ ), 3.84 (s, 3H, 6-OCH ₃ ) 3.69 (t, 2H, N-CH ₂ ), 3.64 (m, 1H, N-CH), 1.73 (m, 4H, 2xCH ₂ ) 1.41 ( s, 9H, 3xCH ₃ ), 1.31 (d, 3H, CH ₃ ); HRMS (ESI): 476.2 (M + 1).

Example 38
2- [4- (2-Cyclohexyl-5,6-dimethoxy-8-quinylamino) pentyl] -1,3-isoindolinedione Yield: 70%; IR (KBr): 3350 cm ^-1 ( NH ₂ ), 1720 cm ^-1 (C = O); ¹ H NMR (CDCl ₃ ): δ 8.22 (d, 1H, 4-Ar-H, .J = 9.2 Hz), 7.75 (m, 4H, Ar- H), 7.46 (d, 1H, 3-Ar-H, J = 9.2 Hz), 6.39 (s, 1H, 7-Ar-H), 6.0 (bs, 1H, NH), 3.96 (s, 3H, 5 -OCH ₃ ), 3.84 (s, 3H, 6-OCH ₃ ) 3.69 (t, 2H, N-CH ₂ ), 3.64 (m, 1H, CH), 1, 75 (m, 4H, 2xCH ₂ ) 1.41 ( m, 10H, 5xCH ₂ ), 1.35 (d, 3H, CH ₃ ); MS (EI): m / z 501 (M ⁺ ) 469.

Example 39
2- [4- (2-Isopropyl-5,6-dimethoxy-8-quinolylamino) pentyl] -1,3-isoindolinedione Yield: 49%; IR (KBr): 3260 cm ^-1 ( NH ₂ ), 1720 cm ^-1 (C = O); ¹ H NMR (CDCl ₃ ): δ 8.10 (d, 1H, 4-Ar-H, J = 7.9 Hz), 7.82 (m, 4H, Ar-H ), 7.40 (m, 5H, Ar-H), 7.37 (dd, 1H, 3-Ar-H, J = 8.0 Hz), 6.84 (s, 1H, 7-Ar-H), 4.81 (bs, 1H, NH), 3.97 (s, 3H, 5-OCH ₃ ), 3.86 (s, 3H, 6-OCH ₃ ) 3.52 (m, 3H, N-CH and N-CH ₂ ), 1.70 (m, 2H, CH ₂ ), 1.46 (m, 2H, CH ₂ ), 1.32 (d, 6H, 2xCH ₃ ), 0.98 (d, 3H, CH ₃ ); MS (EI): m / z 462 (M ⁺ ).

Example 40
2- [4- (2-tert-Butyl-4-ethyl-6-methoxy-5-pentoxy-quinolin-8-ylamino) -pentyl] -isoindole-1,3-dione Yield: 67 %; yellow oil; IR (KBr): 3379 cm ^-1 (NH ₂ ), 1712 (C = O); ¹ H NMR (CDCl ₃ ): 7.82 (m, 2H, Ar-H), 7.71 (m, 2H , Ar-H), 7.10 (d, 1H, 3-Ar-H, J = 4.4 Hz), 6.44 (s, 1H, 7-Ar-H), 6.07 (bs, 1H, NH), 3.96 (s, 3H, OCH ₃ ), 3.87 (t, 2H, OCH ₂ , J = 6.9 Hz), 3.75-3.67 (m, 3H, N-CH, and N-CH ₂ ), 3.24 (m, 2H, CH ₂ ), 1.85-1.41 (m, 10H, 5 xCH ₂ ), 1.34 (s, 9H, 3xCH ₃ ), 1.3 (m, 6H, 2 x CH ₃ ), 0.95 (t, 3H, CH ₃ , J = 7.9 Hz); HRMS (APCI): m / z 560 (M + 1).

Example 41
2- [4- (2-tert-Butyl-4-ethyl-6-methoxy-5-octoxy-quinolin-8-ylamino) -pentyl] -isoindole-1,3-dione Yield: 75 %; yellow oil; IR (KBr): 3407 cm ^-1 (NH ₂ ), 1713 (C = O); ¹ H NMR (CDCl ₃ ): 7.82 (m, 2H, Ar-H), 7.71 (m, 2H , Ar-H), 7.10 (d, 1H, 3-Ar-H, J = 4.4 Hz), 6.44 (s, 1H, 7-Ar-H), 6.07 (bs, 1H, NH), 3.96 (s, 3H, OCH ₃ ), 3.87 (t, 2H, OCH ₂ , J = 6.9 Hz), 3.75-3.67 (m, 3H, N-CH, and N-CH ₂ ), 3.25 (m, 2H, CH ₂ ), 1.89-1.61 (m, 16H, 8 xCH ₂ ), 1.37 (m, 9H, 3xCH ₃ ), 1.30 (m, 6H, 2 xCH ₃ ), 1.04 (t, 3H, CH _3. , J = 7.9 Hz); HRMS (APCI): m / z 602 (M + 1).

Example 42
2- [4- (2-tert-butyl-5,6-methoxy-4-methyl-quinolin-8-ylamino) -pentyl] -isoindole-1,3-dione Yield: 87%; yellow oil; IR (KBr): 3410 cm ^-1 (NH ₂ ), 1713 (C = O); ¹ H NMR (CDCl ₃ ): 7.85 (m, 2H, Ar-H), 7.75 (m, 2H, Ar -H), 7.13 (d, 1H, 3-Ar-H, J = 4.4 Hz), 6.49 (s, 1H, 7-Ar-H), 6.03 (bs, 1H, NH), 4.01 (s, 3H, OCH ₃ ), 3.96 (s, 3H, OCH ₃ ), 3.63 (m, 3H, N-CH, and N-CH ₂ ), 2.59 (t, 2H, CH ₂ ), 1.60 (m 4H, 2xCH ₂ ), 1.34 (s, 9H, 3xCH ₃ ), 1.23 (m, 3H, CH ₃ ); HRMS (APCI): m / z 504 (M + 1).

Ring-substituted ^N 8 - (4-amino-1-methylbutyl) -6-in-methoxy-8-quinoline General Method 95% ethanol for the synthesis of amine (20 mL), ring-substituted 2- [4- (6-methoxy-8- Hydrazine hydrate (100 mmol) was added to a solution of quinolineamino) pentyl] -1,3-isoindolinedione (4 mmol), and the reaction mixture was stirred for 6 hours while refluxing. The solvent was removed under reduced pressure and the residue was diluted with water (20 mL). The reaction mixture was basified with 8N NaOH solution, and extracted with chloroform (3 × 20 mL), washed with water, dried over sodium sulfate, and concentrated under reduced pressure, ring-substituted ^N 8 - (4-amino-1 - methylbutyl) -6-methoxy-8-quinolinamine (14) as an oil, which upon treatment with ethereal hydrochloric acid, ring-substituted ^N 8 - (4-amino-1-methylbutyl) -6-methoxy -8 -Quinolinamine hydrochloride was obtained.

Example 43
N ⁸ - (4-amino-1-methylbutyl) -2-tert-butyl-6-methoxy-8-quinolinamine <br/> Yield: 90%; IR (KBr) : 3393 cm -1 (NH), 3019-2968 cm ^-1 (amine); ¹ H NMR (free base, CDCl ₃ ): δ 7.84 (d, 1H, 4-Ar-H, J = 8.6 Hz), 7.42 (d, 1H, 3-Ar- H, J = 8.5 Hz), 6.30 (dd, 1H, 7-Ar-H, J = 2.3 Hz), 6.25 (dd, 1H, 5-Ar-H, J = 2.2 Hz), 6.16 (bs, 1H, NH), 3.87 (s, 3H, OCH ₃ ), 3.61 (bs, 1H, N-CH), 2.73 (t, 2H, N-CH ₂ ), 1.59 (m, 4H, 2xCH ₂ ), 1.42 (s, 9H, 3xCH ₃ ), 1.31 (d, 3H, CH ₃ ); ¹³ C NMR (CDCl ₃ ): δ 163.36, 158.83, 144.86, 134.96, 133.56, 127.48, 118.80, 96.71, 91.60, 55.19, 47.93, 41.22, 40.59 , 37.70, 33.95, 30.28, 29.69, 27.67, 26.66, 20.72, 20.63; HRMS (ESI): m / z 316 (M + 1).

Example 44
N ⁸ - (4-amino-1-methylbutyl) -5-cyclopentyl-6-methoxy-8-quinolinamine <br/> Yield: 62%; IR (KBr) : 3294cm -1 (NH); 2953-2864 cm ^-1 (amine); ¹ H NMR (free base, CDCl ₃ ): δ 8.59 (d, 1H, 2-Ar-H), 7.94 (d, 1H, 4-Ar-H), 7.26 (m, 1H , 3-Ar-H), 6.67 (s, 1H, 7-Ar-H), 3.89 (s, 3H, OCH ₃ ), 3.71 (m. 1H, N-CH) 3.48 (m, 2H, N-CH ₂ ) 3.12 (m, 1H, CH), 2.64 (m, 4H, 2xCH ₂ ) 1.75 (m, 8H, 4xCH ₂ ), 1.11 (d, 1H, CH ₃ ); MS (EI): m / z 327 ( M ⁺ ).

Example 45
N ⁸ - [4- amino-1-methylbutyl] -2-adamantyl-6-methoxy-8-quinolinamine <br/> Yield: 88%; IR (KBr) : 3384 cm -1 ( amine); ¹ H NMR (free base, CDCl ₃ ): δ 7.86 (d, 1H, 4-Ar-H, J = 8.6 Hz), 7.39 (d, 1H, 3-Ar-H, J = 8.6 Hz), 6.29 (d, 1H, 7-Ar-H), 6.26 (d, 1H, 5-Ar-H), 6.17 (bs, 1H, NH), 3.87 (s, 3H, OCH ₃ ), 3.59 (m, 1H, N-CH ), 2.75 (m, 2H, N-CH ₂ ), 1.97 (m, 15H, 12xCH ₂ and CH) 1.32 (d, 3H, CH ₃ ); ¹³ C NMR (CDCl ₃ ): δ 163.18, 158.84, 45.10, 134.90, 133.86, 127.63, 118.41, 96.43, 91.38, 69.94, 55.19, 48.10, 42.11, 39.30, 38.86, 36.95, 36.56, 34.19, 33.24, 30.17, 29.71, 28.89, 28.01, 20.69, 19.97; HRMS (ESI): 394 (M + 1).

Example 46
N ⁸ - (4-amino-1-methylbutyl) -5-isopropyl-6-methoxy-8-quinolinamine <br/> Yield: 61%; IR (KBr) : 3422 cm -1 (NH); 1 H NMR (free base, CDCl ₃ ): δ 8.61 (d, 1H, 2-Ar-H), 8.1 (d, 1H, 4-Ar-H), 7.61 (dd, 1H, 3-Ar-H), 7.11 (s, 1H, 7-Ar-H), 3.49 (s, 3H, OCH ₃ ), 3.25 (m, 3H, N-CH and N-CH ₂ ), 2.71 (m, 1H, CH), 1.52 (d , 6H, 2xCH ₃ ), 1.15 (d, 3H, CH ₃ ); MS (EI): m / z 301 (M ⁺ ).

Example 47
N ⁸ - (4-amino-1-methylbutyl) -5-cyclohexyl-6-methoxy-8-quinolinamine <br/> Yield: 59%; IR (KBr) : 3417 cm -1 (NH); 1 H NMR (free base, CDCl ₃ ): δ 8.47 (d, 1H, 2-Ar-H), 7.97 (d, 1H, 4-Ar-H), 7.24 (d, 1H, 3-Ar-H), 6.68 (s, 1H, 7-Ar-H), 3.91 (s, 3H, OCH ₃ ), 3.73 (m. 1H, N-CH) 3.48 (m, 2H, N-CH ₂ ) 3.12 (m, 1H, CH ), 2.64 (m, 4H, 2xCH ₂ ) 1.75 (m, 10H, 5xCH ₂ ), 1.11 (d, 1H, CH ₃ ); MS (El): m / z 341 (M ⁺ ).

Example 48
N < ⁸ >-(4-amino-1-methylbutyl) -2,5-dicyclopentyl-6-methoxy-8-quinolinamine Yield: 75%; IR (KBr): 3300 cm < ^-1 > (NH) 2955 cm ^-1 (amine); ¹ H NMR (free base, CDCl ₃ ): δ 7.98 (d, 1H, 4-Ar-H), 7.22 (d, 1H, 3-Ar-H), 6.61 (s , 1H, 7-Ar-H), 3.89 (s, 3H, OCH ₃ ), 3.71 (m. 1H, N-CH) 3.45 (m, 2H, N-CH ₂ ) 3.15 (m, 2H, 2xCH), 2.65 (m, 4H, 2xCH ₂ ) 1.79 (m, 16H, 8xCH ₂ ), 1.2 (d, 1H, CH ₃ ); MS (El): m / z 395 (M ⁺ ).

Example 49
N8- (4-amino-1-methylbutyl) -2,5-diisopropyl-6-methoxy-8-quinolinamine Yield: 79%; IR (KBr): 3430 cm ^-1 (NH); ¹ H NMR (free base, CDCl ₃ ): δ 8.15 (d, 1H, 4-Ar-H), 7.65 (d, 1H, 3-Ar-H), 7.18 (s, 1H, 7-Ar-H), 3.45 (s, 3H, OCH ₃ ), 3.29 (m, 3H, N-CH and N-CH ₂ ), 2.73 (m, 2H, 2xCH), 1.55 (d, 6H, 2xCH ₃ ), 1.54 (d, 6H , 2xCH ₃ ), 1.19 (d, 3H, CH ₃ ); MS (EI): m / z 343 (M ⁺ ).

Example 50
N ⁸ - (4-amino-1-methylbutyl) -2,5-dicyclohexyl-6-methoxy-8-quinolinamine <br/> Yield: 55%; IR (KBr) : 3400 cm -1 (NH); ¹ H NMR (free base, CDCl ₃ ): δ 7.93 (d, 1H, 4-Ar-H), 7.28 (d, 1H, 3-Ar-H), 6.75 (s, 1H, 7-Ar-H) , 3.95 (s, 3H, OCH ₃ ), 3.71 (m. 1H, N-CH) 3.42 (m, 2H, N-CH ₂ ) 3.05 (m, 2H, 2xCH), 2.62 (m, 4H, 2xCH ₂ ) 1.78 (m, 20H, 10xCH ₂ ), 1.15 (d, 1H, CH ₃ ); MS (El): m / z 423 (M ⁺ ).

Example 51
N8- (4-amino-1-methylbutyl) -2-tert-butyl-5,6-dimethoxy-8-quinolinamine Yield: 96%; IR (KBr): 3388 cm- ¹ (NH) , 2958 cm ^-1 (amine); ¹ H NMR (free base, CDCl ₃ ): δ .23 (d, 1H, 4-Ar-H, J = 9 Hz), 7.48 (d, 1H, 3-Ar- H, J = 9Hz), 6.40 (s, 1H, 7-Ar-H), 6.03 (bs, 1H, NH), 3.97 (s, 3H, 5-OCH ₃ ), 3.86 (s, 3H, 6-OCH ₃ ) 3.62 (m, 1H, N-CH), 2.78 (t, 2H, N-CH ₂ ), 1.78 (m, 4H, 2xCH ₂ ), 1.42 (s, 9H, 3xCH ₃ ), 1.33 (d, 3H , CH ₃ ); MS (EI): 345 (M ⁺ ).

Example 52
N8- (4-amino-1-methylbutyl) -2-cyclohexyl-5,6-dimethoxy-8-quinolinamine <br/> Yield: 67%; IR (KBr) : 3310 cm -1 (NH 2); ¹ H NMR (free base, CDCl ₃ ): δ 8.21 (d, 1H, 4-Ar-H, J = 9.2 Hz), 7.49 (d, 1H, 3-Ar-H, J = 9 Hz), 6.41 ( s, 1H, 7-Ar-H), 6.03 (bs, 1H, NH), 3.97 (s, 3H, 5-OCH ₃ ), 3.86 (s, 3H, 6-OCH ₃ ) 3.62 (m, 1H, N -CH), 2.78 (t, 2H, N-CH ₂ ), 1.78 (m, 4H, 2xCH ₂ ), 1.42 (m, 10H, 5xCH ₂ ), 1.31 (d, 3H, CH ₃ ); MS (EI) : m / z 368 (M ⁺ ).

Example 53
N ⁸ - (4-amino-1-methylbutyl) -2-isopropyl-5,6-dimethoxy-8-quinolinamine <br/> Yield: 95%; IR (KBr) : 3330 cm -1 (NH), 2900 cm ^-1 (NH ₂ ); ¹ H NMR (free base, CDCl ₃ ): δ 8.18 (d, 1H, 4-Ar-H, J = 7.8 Hz), 7.35 (m, 1H, 3-Ar-H ), 6.87 (s, 1H, 7-Ar-H), 3.95 (s, 3H, 5-OCH ₃ ), 3.82 (s, 3H, 6-OCH ₃ ) 3.55 (m, 3H, N-CH and N- CH ₂ ), 1.70 (m, 2H, CH ₂ ), 1.46 (m, 2H, CH ₂ ), 1.32 (d, 6H, 2xCH ₃ ), 0.98 (d, 3H, CH ₃ ); HRMS (ESI): m / z 331 (M + 1).

Example 54
N ⁸ - (4-amino-1-methylbutyl) -2-tert-butyl-4-ethyl-6-methoxy-5-pentoxy-8-quinolinamine <br/> Yield: 98%; ¹ H NMR (free Base, CDCl3): δ 6.91 (s, 1H, 3-Ar-H), 6.43 (s, 1H, 7-Ar-H), 3.94 (s, 3H, 5-OCH ₂ ), 3.73 (s, 3H, OCH ₃ ) 2.70 (m, 3H, N-CH and N-CH ₂ ), 2.60 (m, 2H, CH ₂ ), 1.50 (m, 6H, 3xCH ₂ ), 1.34 (s, 9H, 3xCH ₃ ), 1.30 (m, 4H, 2xCH ₂ ), 1.23 (m, 3H, CH ₃ ), 0.96 (m, 3H, CH ₃ ); HRMS (ESI): m / z 430 (M + 1).

Example 55
N ⁸ - (4-amino-1-methylbutyl) -2-tert-butyl-4-ethyl-6-methoxy-5-octyloxy-8-quinoline - amine <br/> Yield: 99%; ¹ H NMR ( Free base, CDCl ₃ ): δ 6.95 (s, 1H, 3-Ar-H), 6.49 (s, 1H, 7-Ar-H), 3.97 (s, 3H, 5-OCH ₂ ), 3.75 (s, 3H, OCH ₃ ) 2.72 (m, 3H, N-CH and N-CH ₂ ), 2.61 (m, 2H, CH ₂ ), 1.53 (m, 10H, 5xCH ₂ ), 1.35 (s, 9H, 3xCH ₃ ) , 1.31 (m, 6H, 3xCH ₂ ), 1.21 (m, 3H, CH ₃ ), 0: 99 (m, 3H, CH ₃ ); HRMS (ESI): m / z 472 (M + 1).

Example 56
N ⁸ - (4-amino-1-methylbutyl) -2-tert-butyl-5,6-methoxy-4-methyl-8-quinolinamine <br/> Yield: 89%; ¹ H NMR (free base, CDCl ₃ ): δ 6.99 (s, 1H, 3-Ar-H), 6.49 (s, 1H, 7-Ar-H), 3.73 (s, 6H, 2xOCH ₃ ) 2.79 (m, 3H, N-CH and N-CH ₂ ), 2.37 (s, 3H, CH ₃ ), 1.53 (m, 4H, 2xCH ₂ ), 1.35 (s, 9H, 3xCH ₃ ), 1.23 (m, 3H, CH ₃ ); HRMS (ESI) : m / z 360 (M + 1).

In the general method of dichloromethane for the synthesis of ring-substituted protected amino acid quinoline derivative (15 mL), ring-substituted ^N 8 - (4-amino-1-methylbutyl) -6-methoxy-8-quinolinamine [(free base), 1 mol] And 1,3-dicyclohexylcarbodiimide (1.1 mol) was added to an ice-cooled stirred solution of amino acid (1.1 mol) appropriately protected with N. The reaction mixture was returned to room temperature and stirring was continued for an additional 4 hours. The reaction mixture was kept in the refrigerator overnight, the separated 1,3-dicyclohexylurea (DCU) was filtered and the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the residue and an additional amount of DCU separated was again filtered off. The filtrate was washed with saturated sodium bicarbonate solution (3 × 10 mL), then water (2 × 10 mL) and dried over Na ₂ SO ₄ . Removal of the solvent under vacuum gave a crude product which was purified by flash column chromatography on silica gel (230-400 mesh) using 2% methanol in chloroform to give the product.

Example 57
{4-Benzyloxycarbonylamino-4- [2-tert-butyl-6-methoxy-quinolin-8-ylamino] -pentyl-carbamoyl} -butyl} -carbamic acid benzyl ester Yield: 98%; IR (KBr): 3430 cm ^-1 (NH), 1714 cm ^-1 (ester), 1666 cm ^-1 (amidocarbonyl); ¹ H NMR (CDCl ₃ ): δ 7.85 (d, 1H, 4-Ar-H , J = 8.6 Hz), 7.42 (d, 1H, 3-Ar-H, J = 8.6 Hz), 7.34 (m, 10H, Ar-H), 6.44 (bs, 1H, NH), 6.29 (s, 3H , 7-Ar-H), 6.24 (s, 1H, 5-Ar-H), 6.12 (bs, 1H, NH), 5.56 (bs, H, NH), 5.50 (bs, 1H, NH), 5.08 ( m, 4H, 2xOCH ₂ Ph), 4.36 (bs, 1H, N-CH), 4.23 (bs, 1H, N-CH), 3.88 (s, 3H, OCH ₃ ), 3.72 (s, 4H, 2xN-CH ₂ ), 3.56 (bs, 1H, N-CH), 3.21 (m, 4H, 2xCH ₂ ), 1.55 (m, 4H, 2xCH ₂ ), 1.42 (s, 9H, 3xCH ₃ ), 1.26 (d, 3H, CH ₃ ); ¹³ C NMR (CDCl ₃ ): δ 172.61, 171.59, 163.35, 158.73, 156.95, 156.40, 155.90, 144.80, 136.22, 134.99, 133.53, 128.22, 128.22, 128.12, 118.83, 96.61, 91.48, 55.16, 53.50 , 52.50 , 47.84, 40.43, 39.66, 37.67, 33.83, 29.91, 29.58, 26.05, 25.89, 20.59, 14.19; HRMS (APCI) m / z 698 (M + 1).

Example 58
{1-4- [2-tert-butyl-6-methoxy-quinolin-8-ylamino] -pentylcarbamoyl} -ethyl} -carbamic acid benzyl ester Yield: 93%; IR (KBr): 3293 cm ^-1 (NH), 1647 (amidocarbonyl); ¹ H NMR (CDCl ₃ ): δ 7.88 (d, 1H, 4-Ar-H, J = 8.5 Hz), 7.44 (d, 1H, 3-Ar- H, J = 8.6 Hz), 7.33 (m, 5H, Ar-H), 6.32 (s, 1H, 7-Ar-H), 6.27 (s, 1H, 5-Ar-H), 5.88 (bs, 1H , NH), 5.34 (bs, 1H, NH), 5.08 (s, 2H, OCH ₂ Ph), 3.87 (s, 4H, OCH ₃ and N-CH), 3.59 (s, 1H, N-CH), 3.30 (s, 2H, N-CH ₂ ), 1.66 (m, 4H, 2xCH ₂ ), 1.42 (s, 9H, 3xCH ₃ ), 1.31 (d, 3H, CH ₃ ), 0.91 (m, 6H, 2xCH ₃ ) ; ¹³ C NMR (CDCl ₃ ): δ 171.03, 158.81, 135.09, 128.17, 118.86, 96.90, 91.63, 67.03, 60.63, 55.20, 48.02, 39.49, 37.70, 33.84, 30.26, 26.08, 25.62, 24.94, 20.57, 19.83, 19.26, 17.71, 14.21; HRMS (ESI) m / z 549 (M + 1).

Example 59
{5-Benzyloxycarbonylamino-5- [4- (2-tert-butyl-6-methoxy-quinolin-8-ylamino) -pentyl-carbamoyl] -pentyl} -carbamic acid benzyl ester Yield: 91%; IR (KBr): 3304 cm ^-1 (NH), 1719 cm ^-1 (ester), 1690 cm ^-1 (amidocarbonyl); ¹ H NMR (CDCl ₃ ): δ 7.86 (d, 1H, 4- Ar-H, J = 8.6 Hz), 7.43 (d, 1H, 3-Ar-H, J = 8.6 Hz), 7.31 (m, 10H, Ar-H), 6.31 (s, 1H, 7-Ar-H ), 6.25 (s, 1H, 5-Ar-H), 6.15 (bs, 1H, NH), 5.50 (bs, 1H, NH), 5.07 (s, 4H, 2xOCH ₂ Ph), 4.82 (bs, 1H, NH), 4.13 (m, 1H, CH), 3.85 (s, 3H, OCH ₃ ), 3.58 (s, 1H, N-CH), 3.27 (s, 2H, N-CH ₂ ), 3.12 (s, 2H , N-CH ₂ ), 1.67 (m, 10H, 5xCH ₂ ), 1.41 (s, 9H, 3xCH ₃ ), 1.25 (d, 3H, CH ₃ ); ¹³ C NMR (CDCl ₃ ): δ 171.52, 163.44, 158.7, 156.63, 156.34, 144.76, 136.59 136.18, 135.07, 133.55, 128.07, 127.53, 118.86, 96.76, 91.63, 67.05, 55.19, 53.50, 47.95, 40.23, 39.48, 33.79, 31.88, 30.26, 29.38, 26.07, 22.31, 20.59, 14.20; HRMS (ESI) m / z 712 (M + 1).

Example 60
{1- [4- (2-tert-butyl-6-methoxy-8-ylamino) -pentylcarbamoyl] -2-methyl-propyl} -carbamic acid) tert-butyl ester Yield: 100%; IR (KBr): 3394 cm ^-1 (NH), 1712 (ester), 1655 (amidocarbonyl); ¹ H NMR (CDCl ₃ ): δ 7.87 (d, 1H, 4-Ar-H, J = 8.5 Hz) , 7.43 (d, 1H, 3-Ar-H, J = 8.3 Hz), 6.31 (s, 1H, 7-Ar-H), 6.25 (s, 1H, 5-Ar-H), 6.20 (bs, 1H , NH), 5.04 (bs, 1H, NH), 4.13 (m, 1H, N-CH), 3.87 (s, 3H, OCH ₃ ), 3.60 (m, 1H, N-CH), 3.30 (m, 2H , N-CH ₂ ) 1.68 (m, 4H, 2xCH ₂ ), 1.42 (s, 9H, 3xCH ₃ ), 1.39 (s, 9H, 3xCH ₃ ), 1.31 (d, 4H, 2xCH ₂ ); ¹³ C NMR ( CDCl ₃ ): δ 172.55, 163.35, 158.7, 155.55, 144.84, 135.00.133.58, 127.49, 118.49, 118.80, 96.66, 91.50, 60.41, 54.74, 50.83, 50-18, 49.14, 47.93, 39.44, 37.69, 33.95, 32.66 , 31.71, 30.27, 28.30, 29.38, 26.18, 25.62, 25.51, 25.36, 21.05, 20.64, 18.61, 14.20; HRMS (ESI) m / z 487 (M + 1).

General Methods for the Synthesis of Ring-Substituted N ^1- [4- (6-Methoxy-8-quinolylamino) pentyl]-(2S) -2-amino / diaminoalkanamide Ring-substituted benzyl ester (0 0.5 mmol), glacial acetic acid (1 mL) and 10% Pd-C (0.1 g) were passed through hydrogen gas for 1 hour. The catalyst was filtered and the filtrate was concentrated in vacuo to give the product as an oily syrup, which was treated with ethereal HCl solution to give the corresponding hydrochloride derivative.

  Alternatively, when including the use of a t-Boc protected amino acid, a solution of the protected derivative (0.5 mmol) in methanolic hydrogen chloride (20 mL) was stirred overnight at room temperature. The solvent was removed under vacuum to give an orange solid. This was recrystallized from methanol / diethyl ether.

Example 61
^{N 1 - [4- (2-} tert- butyl-6-methoxy-8-Kinoriruamino) pentyl] - (2S) -2,5- diaminopentane amide <br/> Yield: 99%; IR (KBr) : 3018 cm ^-1 (NH ₂ ); ¹ H NMR (free base, CDCl ₃ ): δ 8.92 (bs, 4H, 2xNH ₂ ), 7.85 (d, 1H, 4-Ar-H), 7.42 (d, 1H, 3-Ar-H), 6.30 (bs, 1H, 7-Ar-H), 6.23 (s, 1H, 5-Ar-H), 3.85 (s, 3H, OCH ₃ ), 3.58 (s, 1H, N -CH), 3.44 (s, 1H, N-CH), 3.25 (s, 4H, 2xN-CH ₂ ), 2.95 (m, 4H, 2xCH ₂ ), 1.40 (s, 9H, 3xCH ₃ ), 1.26 (d , 3H, CH ₃ ); ¹³ C NMR (CDCl ₃ ): δ 177.38, 170.11, 163.32, 158.79, 144.85, 134.99, 133.57, 127.47, 118.79, 96.61, 91.46, 55.13, 52.68, 49.67, 47.82, 41.74, 39.78, 39.74, 37.66, 34.11, 33.67, 30.24, 28.90, 25.85, 24.85, 22.98, 22.16, 20.73; HRMS (ESI) m / z 429 (M + 1).

Example 62
^{N 1 - [4- (2-} tert- butyl-6-methoxy-8-Kinoriruamino) pentyl] - (2S)-2-amino-3-methyl - butanamide <br/> Yield: 94%; IR (KBr ): 3243 cm ^-1 (NH ₂ ), 1663 cm ^-1 (CONH); ¹ H NMR (free base, CDCl ₃ ): δ 7.86 (d, 1H, 4-Ar-H, J = 8.5 Hz), 7.61 (bs, 1H, NH), 7.43 (d, 1H, 3-Ar-H, J = 8.5 Hz), 6.31 (s, 1H, 7-Ar-H), 6.26 (s, 1H, 5-Ar-H ), 3.87 (s, 3H, OCH ₃ ), 3.62 (s, 1H, N-CH) 3.35 (m, 2H, N-CH ₂ ), 2.72 (s, 1H, N-CH), 1.68 (m, 4H , 2xCH ₂ ), 1.41 (s, 9H, 3xCH ₃ ), 1.29 (d, 3H, CH ₃ ), 0.945 (m, 6H, 2xCH ₃ ); ¹³ C NMR (CDCl ₃ ): δ 176.68, 171.63, 163.34, 158.86, 144.89, 134.98, 133.6, 127.49, 118.79, 96.69, 91.50, 67.47, 55.17, 47.90, 43.02, 39.24, 37.69, 34.16, 33.74, 30.80, 30.27, 26.16.25.56, 24.87, 21.50, 20.65, 19.39, 18.90, 18.23, 16.57, 13.94; HRMS (ESI) m / z 414 (M + 1).

Example 63
^{N 1 - [4- (2-} tert- butyl-6-methoxy-8-Kinoriruamino) pentyl] - (2S) -2-6- diaminohexane amide <br/> Yield: 100%; IR (KBr) : 3435 cm ^-1 (NH ₂ ), 1667 cm- (amidocarbonyl); ¹ H NMR (fiee base, CDCl ₃ ): δ 7.85 (d, 1H, 4-Ar-H, J = 8.5 Hz), 7.42 (d , 1H, 3-Ar-H, J = 8.5 Hz), 6.29 (s, 1H, 7-Ar-H), 6.24 (s, 1H, 5-Ar-H), 5.64 (bs, 4H, 2xNH ₂ ) , 3.89 (s, 3H, OCH ₃ ), 3.68 (s, 1H, N-CH), 3.24 (m, 4H, 2xN-CH ₂ ), 2.87 (bs, 1H, N-CH), 1.63 (m, 10H , 2xCH ₂ ), 1.41 (s, 9H, 3xCH ₃ ), 1.24 (d, 3H, CH); HRMS (ESI) m / z 444 (M + 1).

Example 64
^{N 1 - [4- (2-} tert- butyl-6-methoxy-8-Kinoriruamino) pentyl] - (2S) -2- amino-propanamide <br/> Yield: 98%; IR (KBr) : 3018 cm ^-1 (NH ₂ ), 1710 cm ^-1 (amidocarbonyl); ¹ H NMR (free base, CDCl ₃ ): δ 7.86 (d, 1H, 4-Ar-H), 7.65 (d, 1H, 3-Ar -H), 7.15 (s, 1H, 7-Ar-H), 6.81 (s, 1H, 5-Ar-H), 5.48 (bs, 1H, NH), 4.3 (bs, 1H, NH), 3.99 ( m, 1H, N-CH), 3.71 (m, 1H, N-CH), 1.84 (m, 4H, 2xCH ₂ ), 1.50 (s, 9H, 3xCH ₃ ), 1.25 (d, 6H, 2xCH ₃ ); HRMS (ESI) m / z 387 (M + 1).

Advantages 1. This compound has been shown to be successful in treating recurrent malaria.
2. This molecule is easy to synthesize and is not expensive to manufacture.
3.8-Aminoquinoline analogs are active against all stages, including the blood and tissue phases of the human malaria life cycle.
4). This molecule is effective against drug-resistant strains of Plasmodium falciparum.
5. The most effective molecules are also free of the methemoglobin toxicity previously associated with the 8-aminoquinoline class of antimalarials.

Claims (34)

Ring substituted 8-aminoquinoline analogs of formula 1:

[Wherein R is H, a linear alkoxy group containing 1 to 8 carbon atoms, a branched alkyl group containing 3 to 7 carbon atoms, a cycloalkyl group containing 3 to 15 carbon atoms, Represents phenoxy and substituted phenoxy groups, R ₁ represents H, CH ₃ and C ₂ H ₅ , R ₂ represents CH (CH ₃ ) ₂ , C (CH ₃ ) ₃ , c-C ₅ H ₉ , c- C ₆ H ₁₁ or adamantyl, R ₃ represents H, Val, Lys, Ala or Orn]. R, R ₁ , R ₂ and R ₃ of the compound of formula 1 are:

The ring-substituted 8-aminoquinoline analog of claim 1, which is shown in Compounds of formula 1, for 4 days at a dose ranging from 10-100 mg, is effective against Plasmodium berghei (Plasmodium berghei) infections, ring-substituted 8-aminoquinoline analog of claim 1. Compounds of formula 1, for 4 days at a dose ranging from 10-100 mg, is effective against Plasmodium yoelii (Plasmodium yoelii) infection, ring-substituted 8-aminoquinoline analog of claim 1. The ring-substituted 8-aminoquinoline analog of claim 1, wherein the compound of Formula 1 has an LD ₅₀ of 400 mg / kg body weight. The ring-substituted 8-aminoquinoline analog of claim 1, wherein the compound of formula 1 has an IC ₅₀ of 39.06 ng / ml.   2. The ring-substituted 8-aminoquinoline analog of claim 1, wherein the analog is free of methemoglobin (MetHb) toxicity.   The ring-substituted 8-aminoquinoline analogue according to claim 1, wherein the analogue has a broad range of antimalarial activity with respect to the blood stage and tissue stage of the malaria parasite.   The ring-substituted 8-aminoquinoline analog of claim 1, wherein the analog is effective against a resistant strain of human malaria parasite. An antimalarial composition comprising a pharmaceutically effective amount of a ring-substituted 8-aminoquinoline analog of formula 1 and a pharmacologically acceptable additive:

[Wherein R is H, a linear alkoxy group containing 1 to 8 carbon atoms, a branched alkyl group containing 3 to 7 carbon atoms, a cycloalkyl group containing 3 to 15 carbon atoms, Represents phenoxy and substituted phenoxy groups, R ₁ represents H, CH ₃ and C ₂ H ₅ , R ₂ represents CH (CH ₃ ) ₂ , C (CH ₃ ) ₃ , c-C ₅ H ₉ , c- C ₆ H ₁₁ or adamantyl, R ₃ represents H, Val, Lys, Ala or Orn].   Pharmaceutically acceptable additives are from the group of lactose, mannitol, sorbitol, microcrystalline cellulose, sucrose, sodium citrate, dicalcium phosphate or any other component of similar nature, or suitable combinations thereof A binder selected from the group of acceptable diluents selected, gum tragacanth, gum arabic, methylcellulose, gelatin, polyvinylpyrrolidone, starch or any other component of similar nature, or suitable combinations thereof, agar, An excipient selected from the group of calcium carbonate, sodium carbonate, silicate, alginic acid, corn starch, potato tapioca starch, primogel or any other component of similar nature, or suitable combinations thereof, magnesium stearate, Calcium stearate or Lubricant, acetyl alcohol, glyceryl monostearate or any other pharmaceutically acceptable selected from the group of steolot, talc, solid polyethylene glycol, sodium lauryl sulfate or any other component of similar nature Absorbents, waxes, paraffins selected from the group of humectants, kaolin, bentonite clay or any other pharmaceutically acceptable flavor, or preferred combinations thereof selected from the group of flavors, or preferred combinations thereof 11. The antimalarial composition of claim 10, which is a retarder selected from the group of or any other pharmaceutically acceptable flavor, or suitable combinations thereof. R, R ₁ , R ₂ and R ₃ of the compound of formula 1 are:

11. The antimalarial composition of claim 10, comprising a ring-substituted 8-aminoquinoline analog that is shown in   The antimalarial composition according to claim 10, wherein the composition has a broad range of antimalarial activity with respect to a blood stage and a tissue stage of a malaria parasite.   11. The antimalarial composition according to claim 10, wherein the composition is effective against a resistant strain of human malaria parasite. 11. The antimalarial composition of claim 10, wherein the compound of formula 1 has an IC ₅₀ of 39.06 ng / ml. Ring-substituted 8-aminoquinoline analogs of Formula 1, 4 days at doses ranging from 10-100 mg, is effective against Plasmodium berghei (P. berghei) infections, antimalarial composition according to claim 10 . Ring-substituted 8-aminoquinoline analogs of Formula 1, 4 days at doses ranging from 10-100 mg, is effective against Plasmodium yoelii (P. yoelii) infection, antimalarial composition according to claim 10 . 11. The antimalarial composition according to claim 10, wherein the compound of formula 1 has an LD ₅₀ of 400 mg / kg body weight.   11. The antimalarial composition of claim 10, wherein the ring substituted 8-aminoquinoline analog of Formula 1 is free of methemoglobin (MetHb) toxicity.   The composition according to claim 10, which is in the form of a syrup, tablet, capsule, powder or injection. Scheme 1 :

[Wherein R is H, a linear alkoxy group containing 1 to 8 carbon atoms, a branched alkyl group containing 3 to 7 carbon atoms, a cycloalkyl group containing 3 to 15 carbon atoms, Represents phenoxy and substituted phenoxy groups, R ₁ represents H, CH ₃ and C ₂ H ₅ , R ₂ represents CH (CH ₃ ) ₂ , C (CH ₃ ) ₃ , c-C ₅ H ₉ , c- C ₆ H ₁₁ or adamantyl, R ₃ represents H, Val, Lys, Ala or Orn]
According to claim 1 , wherein the salt-forming acid is essentially organic or inorganic, wherein the salt-forming acid is essentially organic or inorganic. May be,
a (i in Scheme 1) . 8-nitroquinoline and an alkyl carboxylic acid are reacted in an aprotic solvent in the presence of sulfuric acid, silver nitrate and ammonium persulfate at a reflux temperature for a time ranging from 5 minutes to 1 hour, and from the reaction mixture, ring substitution 8 -Isolating the nitroquinoline ,
b (ii in Scheme 1) . Reacting the ring-substituted 8- nitroquinoline obtained in step (a) with a catalyst and hydrogen under pressure to obtain a ring-substituted 8 - aminoquinoline;
c (iii in Scheme 1) . The obtained ring-substituted 8 - aminoquinoline is reacted with 2- (4-bromopentyl) -1,3-isoindolinedione and triethylamine at a temperature in the range of 100 to 140 ° C. for a time in the range of 3 to 8 hours. Obtaining an isoindolinedione derivative,
d (iv in Scheme 1) . Step and isoindoline-dione derivative with hydrazine hydrate obtained in (c) are reacted in an alcoholic solvent ring-substituted N ⁸ - to produce a (4-amino-1-methylbutyl) -8-quinolinamine , And e (iv in Scheme 1) . ^N 8 obtained in step (d) - and (4-amino-1-methylbutyl) 8-quinolinamine and N- protected amino acid and dicyclohexyl carbodiimide in chloroalkanes solvent, at a temperature ranging from 10 to 50 ° C. A method comprising the steps of reacting and isolating a ring-substituted protected amino acid quinoline derivative, followed by deprotecting the amino acid portion of the molecule to obtain a compound of formula 1.   The method of claim 21, wherein the alkyl carboxylic acid is selected from the group consisting of trimethylacetic acid, isobutyric acid, cyclohexanecarboxylic acid, and 1-adamantanecarboxylic acid.   The 8-nitroquinoline is 6-methoxy-8-nitroquinoline, 5,6-dimethoxy-8-nitroquinoline, 4-ethyl-5-pentoxy-6-methoxy-8-nitroquinoline, 4-ethyl-5- The method according to claim 21, wherein the method is selected from octoxy-6-methoxy-8-nitroquinoline and 4-methyl-5,6-dimethoxy-8-nitroquinoline.   The method according to claim 21, wherein the catalyst used in the reduction step (b) is Raney nickel. The reduction is carried out at a pressure in the range of 40~50psi at Pal (Parr) hydrogenation apparatus, method according to claim 21.   The method according to claim 21, wherein the alcohol solvent is ethyl alcohol.   The method of claim 21, wherein the chloroalkane solvent is dichloromethane.   The method according to claim 21, wherein the deprotection of the benzyl ester of the amino acid part of the molecule in step (e) is carried out in the presence of Pd-C in methanol in the presence of hydrogen gas.   The method of claim 21, wherein the deprotection of the t-Boc protected amino acid is performed in the presence of methanolic HCl. R, R ₁ , R ₂ and R _{3 of} formula 1 are

The method of claim 21, which is shown in Compounds of formula 1, for 4 days at a dose ranging from 10-100 mg, Plasmodium berghei (P. berghei), is effective against Plasmodium yoelii (P. yoelii) infection The method of claim 21. The method of claim 21, wherein the compound of formula 1 has an LD ₅₀ of 400 mg / kg body weight.   24. The method of claim 21, wherein the ring-substituted 8-aminoquinoline analog is free of methemoglobin (MetHb) toxicity. The method of claim 21, wherein the compound of Formula 1 has an IC ₅₀ of 39.06 ng / ml.